![Page 1: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/1.jpg)
Sequence Homology
Treat or Trick?
Fine Grain Structural Classification using the T-RMSD method
Cedric NotredameLuis SerranoCedrik MagisFrançois StricherAlmer van der Slot
![Page 2: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/2.jpg)
Same sequence Same structure
SameFunctio
n
SameOrigin
Same3D fold
SameSequen
ce
![Page 3: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/3.jpg)
Same sequence Same structure ???
100% IdenticalSequence
Prion proteinPrP-c
(normal)
>P04156|23-230 / PRIO_HUMANKKRPKPGGWNTGGSRYPGQGSPGGNRYPPQGGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQGGGTHSQWNKPSKPKTNMKHMAGAAAAGAVVGGLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYYQRGS
Prion proteinPrP-sc
(pathology)
100% IdenticalSequence
![Page 4: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/4.jpg)
TNF Receptors (TNFRs)
Aggarwal, BB. Nat Rev Immunol. 2003 Sep;3(9):745-56.
Receptor Ligand
Intra Extra
![Page 5: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/5.jpg)
TNFRs: The Cystein Rich Domains (CRDs)
Turn1
Loop1
Turn2
Loop2
![Page 6: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/6.jpg)
TNFR and CRD Collections
Domain Databases
34
25 annotatednot identified
010
4
1
217
6 putatives not identified
UNIPROT
![Page 7: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/7.jpg)
This suggests the CRDs are homogenous
![Page 8: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/8.jpg)
Is it supported by 3D Superposition ?
![Page 9: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/9.jpg)
Classifications
If they are so different and diverse– Can we classify them?– Can this classification bring functional information?
![Page 10: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/10.jpg)
Structurally?
Not really…
![Page 11: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/11.jpg)
Phylogeny?
Not quite there…
![Page 12: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/12.jpg)
Add-hoc?
Maybe…
![Page 13: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/13.jpg)
Add-hoc?
Maybe…Bodmer, JL., Schneider, P., Tschopp, J. Trends Biochem. Sci. 2002 Jan;27(1):19-26.
![Page 14: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/14.jpg)
Add-hoc?
Half Domains Complex Explains Little
Maybe…
![Page 15: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/15.jpg)
A new Classification ?
Is it possible to design a new classification– Structure based – Functionally informative– Predictive for TNFRs without a known structure
Yes if we can compare structures in a more informative way
![Page 16: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/16.jpg)
The Standard Way: RMSD(Root Mean Square Deviation)
RMSD– Superpose the
Structures– Measure The deviation
D1 D2
D3
Y
X
W
Z
![Page 17: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/17.jpg)
A Simpler Alternative: the iRMSD
D2
D1
D1
D2
![Page 18: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/18.jpg)
T-RMSD: Trees based on iRMSD
d1
DistanceMatrix
P1
P1
UPGMAA
B
C
D
B
d2
ABCD
![Page 19: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/19.jpg)
T-RMSD: Trees based on iRMSD
d1 d2
Consensus Tree
P1
A
B
C
D
C
B
A
D
A
B
C
D
C
B
A
D
ABCD
![Page 20: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/20.jpg)
T-RMSD Vs Clustering
![Page 21: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/21.jpg)
T-RMSD Vs Clustering
![Page 22: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/22.jpg)
Does The Clustering Make Sense ?
![Page 23: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/23.jpg)
Well Conserved Inserts ?
![Page 24: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/24.jpg)
What Does the New Classification Predict ?
Type IType IIType IIIOutliers
![Page 25: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/25.jpg)
What Does the New Classification Predict ?
Type IType IIType IIIOutliers
Nter CRDs (Pre Ligand Assembly
Domains, PLAD) are involved in the
complex formation
![Page 26: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/26.jpg)
Next ???
New Classes ? New Functions ? New Structures
???
![Page 27: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/27.jpg)
Next ???
Which Ligand How To Align These
things– MSA problem???
![Page 28: Sequence Homology Treat or Trick? Fine Grain Structural Classification using the T-RMSD method Cedric Notredame Luis Serrano Cedrik Magis François Stricher](https://reader035.vdocument.in/reader035/viewer/2022081516/5697bffa1a28abf838cc0926/html5/thumbnails/28.jpg)
Summary
T-RMSD– Fine Grain Structural Classification
TNFRs/CRD– New typology– Structurally meaningful– Functionally informative– Predictive
T-RMSD is available for download and part of the T-Coffee package (www.tcoffee.org)
Collaborators
– Cedrik Magis– François Stricher– Almer van der Slot– Luis Serrano– Cedric Notredame