from protein structure to function. the particular catalytic activity, binding properties or...
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The particular catalytic activity, binding properties or conformational changes of a protein.
The complex, or metabolic or signal transduction pathway in which a protein participates
Gene duplication – with two copies of a gene, one can retain its function while the other can assume a new biological role.
Gene fusion – two genes are combined and activated by the same promoter
One Gene – to or more functions Post translational modifications Alternate splicing
With high throughput crystallization techniques, structure can be determined more easily than function
40
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0 10 20 30 40 50 60 70 80 90 100
sequence idenity (%)
SS
AP
sco
re
Different Function
Same Function
Conservation of Enzyme Function in CATH Domain FamiliesConservation of Enzyme Function in CATH Domain Families
Pairwise sequence identity
Str
uct
ura
l si
mila
rity
(S
SA
P)
score
same functions different functions
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90 100
sequence idenity (%)
SS
AP
sco
re
Different Function
Same Function
Pairwise sequence identity
Str
uct
ura
l si
mila
rity
(S
SA
P)
score
same functions different functions
Build a interaction network Model response of gene to changes in
promoter concentration Simulate the system to determine
influence of gene product on system
Complex systems of simple elements have functions that emerge from the properties of the networks they form.
Biological systems have functions that rely on a combination of the network and the specific elements involved.
In molecular biology, gene structure and function is studied at the molecular level.
In systems biology, specific interactions of components in the biological system are studied – cells, tissues, organs, and ecological webs.
Biological Systems are complex, thus, a combination of experimental and computational approaches are needed.
Linkages need to be made between molecular characteristics and systems biology results
Languages Systems Biology Markup Language CellML Systems Biology Workbench
Databases Kyoto Encyclopedia of Genes and Genomes Alliance for Cellular Signaling Signal Transduction Knowledge Environment
Protein 53 Guardian of the genome Detects DNA damages Halts the cell cycle if damage is detected
to give DNA time to repair itself
If (damage equals true and repairable = true)
halt cell cycle else
if(damage equals true and repairable = false) induce apoptosis (suicide)
G1 - Growth and preparation of the chromosome replication
S - DNA replication
G2 - Preparation for Mitosis
M - Chromosomes separate
Alkylating agents - interfere with cell division and affect the cancer cells in all phases of their life cycle. They confuse the DNA by directly reacting with it.
Antimetabolites - interfere with the cell's ability for normal metabolism. They either give the cells wrong information or block the formation of "building block" chemical reactions one phase of the cell's life cycle.
Vinca alkaloids - (plant alkaloids) are naturally-occurring chemicals that stop cell division in a specific phase.
Taxanes - are derived from natural substances in yew trees. They disrupt a network inside cancer cells that is needed for the cells to divide and grow.
all inhibit the cell cycle
NOBLE, D (2002) Nature Reviews Molecular Cell Biology 3, 460-463.
Unravelling complexityNeed to work in an integrative way at all levels:
organism organtissue
cellular sub-cellularpathwaysprotein
gene
There are feed-downs as well as upward between all these levels
higher levels controlgene expression
higher levels controlcell function &
pathways
Heart Model Construction 2000
INa
IClIK1 IK Ito
ICa
Channels
I Na/K
I NaCaNa/H Na/HCO3 Cl/OH
Cl/HCO3
Carriers
Ca
pH
ATP
Glucose
Fatty Acids
Amino Acids
H/Lactate
SubstratesAng II1
2
NO
ßM
Receptors
Example of protein interaction in a cell model Reconstructing the heart’s pacemaker
Sinus rhythm generated by ion channel interaction
ICaL
IKr
Em
If is example of fail-safe ‘redundancy’
Rhythm abolished when interaction prevented
Acceleration of sinus rhythm by adrenaline
If
All 3 protein levels up-regulated
Disease insightModelling arrhythmias
Mutations in various ionic channels can predispose to repolarization failure
This simulation is of a sodium channelmis-sense mutation responsible foridiopathic ventricular fibrillation
Computer model prediction
• Sodium channel missense mutation
• 12 and 18 mV voltage shifts
• Using digital cell ventricular model
12 mVshift18 mVshift
This approach has now been used for a substantial number of gene manipulations in heart cells and can account for genetic susceptibility to fatal cardiac arrhythmia
Including interactions with drugs causing long QT and arrhythmia in clinical trials
Genetic typing to screen out those susceptible to drugs causingQT problems is therefore a foreseeable possibility
Noble D (2002) Unravelling the genetics and mechanisms of cardiac arrhythmia. Proc Natl Acad Sci USA 99, 5755-6
Unravelling genetics of arrhythmia