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Cloning Expression Purification and Enzymological Characterization of NS2B(H)NS3 protease of Japanese Encephalitis Virus
Chakard Chalayut
Advisor Assit Prof Gerd Katzenmier
Laboratory of Molecular Virology Institute of Molecular Biology amp Genetics
1
Japanese Encephalitis Virus
Flaviviridae familyDengue (Den)
West nile virus (WNV)
Yellow fever virus (YFV)
Japanese Encephalitis Virus (JEV)
ETC
2
Japanese Encephalitis Virus
Flaviviridae familyDengue (Den)
West nile virus (WNV)
Yellow fever virus (YFV)
Japanese Encephalitis Virus (JEV)
ETC
2
Japanese Encephalitis Virus
Mosquito-borne neurotropic flavivirus
causes severe central nerve system diseases
Divided into 4 Genotypes
For unknown reason genotypes 3 is the most outbreak
Culex tritaeniorhynchus is the important vector
httpwwwfehdgovhk
3
Japanese Encephalitis Virus
httpwwwfehdgovhk
3
Japanese Encephalitis Virus
4
Japanese Encephalitis Virus
JEV causes severe central nerve system d i s e a s e s s u c h a s poliomyelitis- like acute flaccid paralysis aseptic m e n i n g i t i s a n d encephalitis
httpwwwwondercdcgov
4
Japanese Encephalitis Virus
httpwwwcdcgov
4
Japanese Encephalitis Virus
50000 casesyear
4
Japanese Encephalitis Virus
10000 Death Casesyear
4
Japanese Encephalitis Virus
30 fatality rate
4
Prevention and treatment of JEV disease
5
Prevention and treatment of JEV disease
Drug
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Japanese Encephalitis Virus
Flaviviridae familyDengue (Den)
West nile virus (WNV)
Yellow fever virus (YFV)
Japanese Encephalitis Virus (JEV)
ETC
2
Japanese Encephalitis Virus
Flaviviridae familyDengue (Den)
West nile virus (WNV)
Yellow fever virus (YFV)
Japanese Encephalitis Virus (JEV)
ETC
2
Japanese Encephalitis Virus
Mosquito-borne neurotropic flavivirus
causes severe central nerve system diseases
Divided into 4 Genotypes
For unknown reason genotypes 3 is the most outbreak
Culex tritaeniorhynchus is the important vector
httpwwwfehdgovhk
3
Japanese Encephalitis Virus
httpwwwfehdgovhk
3
Japanese Encephalitis Virus
4
Japanese Encephalitis Virus
JEV causes severe central nerve system d i s e a s e s s u c h a s poliomyelitis- like acute flaccid paralysis aseptic m e n i n g i t i s a n d encephalitis
httpwwwwondercdcgov
4
Japanese Encephalitis Virus
httpwwwcdcgov
4
Japanese Encephalitis Virus
50000 casesyear
4
Japanese Encephalitis Virus
10000 Death Casesyear
4
Japanese Encephalitis Virus
30 fatality rate
4
Prevention and treatment of JEV disease
5
Prevention and treatment of JEV disease
Drug
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Japanese Encephalitis Virus
Flaviviridae familyDengue (Den)
West nile virus (WNV)
Yellow fever virus (YFV)
Japanese Encephalitis Virus (JEV)
ETC
2
Japanese Encephalitis Virus
Mosquito-borne neurotropic flavivirus
causes severe central nerve system diseases
Divided into 4 Genotypes
For unknown reason genotypes 3 is the most outbreak
Culex tritaeniorhynchus is the important vector
httpwwwfehdgovhk
3
Japanese Encephalitis Virus
httpwwwfehdgovhk
3
Japanese Encephalitis Virus
4
Japanese Encephalitis Virus
JEV causes severe central nerve system d i s e a s e s s u c h a s poliomyelitis- like acute flaccid paralysis aseptic m e n i n g i t i s a n d encephalitis
httpwwwwondercdcgov
4
Japanese Encephalitis Virus
httpwwwcdcgov
4
Japanese Encephalitis Virus
50000 casesyear
4
Japanese Encephalitis Virus
10000 Death Casesyear
4
Japanese Encephalitis Virus
30 fatality rate
4
Prevention and treatment of JEV disease
5
Prevention and treatment of JEV disease
Drug
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Japanese Encephalitis Virus
Mosquito-borne neurotropic flavivirus
causes severe central nerve system diseases
Divided into 4 Genotypes
For unknown reason genotypes 3 is the most outbreak
Culex tritaeniorhynchus is the important vector
httpwwwfehdgovhk
3
Japanese Encephalitis Virus
httpwwwfehdgovhk
3
Japanese Encephalitis Virus
4
Japanese Encephalitis Virus
JEV causes severe central nerve system d i s e a s e s s u c h a s poliomyelitis- like acute flaccid paralysis aseptic m e n i n g i t i s a n d encephalitis
httpwwwwondercdcgov
4
Japanese Encephalitis Virus
httpwwwcdcgov
4
Japanese Encephalitis Virus
50000 casesyear
4
Japanese Encephalitis Virus
10000 Death Casesyear
4
Japanese Encephalitis Virus
30 fatality rate
4
Prevention and treatment of JEV disease
5
Prevention and treatment of JEV disease
Drug
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Japanese Encephalitis Virus
httpwwwfehdgovhk
3
Japanese Encephalitis Virus
4
Japanese Encephalitis Virus
JEV causes severe central nerve system d i s e a s e s s u c h a s poliomyelitis- like acute flaccid paralysis aseptic m e n i n g i t i s a n d encephalitis
httpwwwwondercdcgov
4
Japanese Encephalitis Virus
httpwwwcdcgov
4
Japanese Encephalitis Virus
50000 casesyear
4
Japanese Encephalitis Virus
10000 Death Casesyear
4
Japanese Encephalitis Virus
30 fatality rate
4
Prevention and treatment of JEV disease
5
Prevention and treatment of JEV disease
Drug
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Japanese Encephalitis Virus
4
Japanese Encephalitis Virus
JEV causes severe central nerve system d i s e a s e s s u c h a s poliomyelitis- like acute flaccid paralysis aseptic m e n i n g i t i s a n d encephalitis
httpwwwwondercdcgov
4
Japanese Encephalitis Virus
httpwwwcdcgov
4
Japanese Encephalitis Virus
50000 casesyear
4
Japanese Encephalitis Virus
10000 Death Casesyear
4
Japanese Encephalitis Virus
30 fatality rate
4
Prevention and treatment of JEV disease
5
Prevention and treatment of JEV disease
Drug
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Japanese Encephalitis Virus
JEV causes severe central nerve system d i s e a s e s s u c h a s poliomyelitis- like acute flaccid paralysis aseptic m e n i n g i t i s a n d encephalitis
httpwwwwondercdcgov
4
Japanese Encephalitis Virus
httpwwwcdcgov
4
Japanese Encephalitis Virus
50000 casesyear
4
Japanese Encephalitis Virus
10000 Death Casesyear
4
Japanese Encephalitis Virus
30 fatality rate
4
Prevention and treatment of JEV disease
5
Prevention and treatment of JEV disease
Drug
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Japanese Encephalitis Virus
httpwwwcdcgov
4
Japanese Encephalitis Virus
50000 casesyear
4
Japanese Encephalitis Virus
10000 Death Casesyear
4
Japanese Encephalitis Virus
30 fatality rate
4
Prevention and treatment of JEV disease
5
Prevention and treatment of JEV disease
Drug
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Japanese Encephalitis Virus
50000 casesyear
4
Japanese Encephalitis Virus
10000 Death Casesyear
4
Japanese Encephalitis Virus
30 fatality rate
4
Prevention and treatment of JEV disease
5
Prevention and treatment of JEV disease
Drug
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Japanese Encephalitis Virus
10000 Death Casesyear
4
Japanese Encephalitis Virus
30 fatality rate
4
Prevention and treatment of JEV disease
5
Prevention and treatment of JEV disease
Drug
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Japanese Encephalitis Virus
30 fatality rate
4
Prevention and treatment of JEV disease
5
Prevention and treatment of JEV disease
Drug
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Prevention and treatment of JEV disease
5
Prevention and treatment of JEV disease
Drug
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Prevention and treatment of JEV disease
Drug
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control
Available vaccine
5
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Prevention and treatment of JEV disease
Drug No drug exist
Vaccine development
Mosquitoes control Elimination of mosquitoes
breeding places
Available vaccine
5
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Molecular biology of Japanese Encephalitis Virus
www molecular-virologyuni-hdde6
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
The NS2B130 aa
activating domain central hydrophilic region (Falgout et al 1993)
3 membrane spanning parts Hypothetical model NS2B-NS3 complex
7
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 19997
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
The NS2B
Hypothetical model NS2B-NS3 complex
Brinkworth et al 199958 VSGKATDMWLERAADISWEMDAAITGSSRRLDVKLDDDGDFHLIDDPGVP 101
7
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
The NS3
Theoretical model from PDB 2I84
8
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
The NS3
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
The NS3
NTPase
Protease
Theoretical model from PDB 2I84
8
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
The NS3
NTPase
Protease
RNA Helicase
Theoretical model from PDB 2I84
8
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
The NS3
Chymotrypsin-like fold2-β barrel domains
Inactive aloneEnzymersquos pocket is small
8
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
The NS3 protease
9
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
The NS3 protease
conformational changealteration of the enzyme pocket additional substrate binding site
Complexation with NS2B cofactor
9
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
The NS3 protease
NS3 serine protease domain 20 kDacatalytic residues His51 Asp75 Ser135
9
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Lin C W et al200710
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Ser46 to Ile60 were essential region required for NS3 protease activity
Ala substition of Trp50 Glu55 and Arg56 in NS2B shown significantly reduced NS3 protease activity
Lin C W et al200710
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Compare to the structure
WNV
JEV homology model from Den
JEV
Den 2
11
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
Report
From Novartis
Den 2 protease can be activated by Den123 WNV and YFV NS2B(H)
From Jan LR et al 1995
Den 4 protease canrsquot be activated by JEV NS2B(H) but JEV protease can activated by Den 4 NS2B(H)
12
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
From the different on NS2B(H)-NS3 protease complex structure and cofactor specificityCan we do the NS2B cofactor analog as an universal drug for flavivirus
13
top related