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MarkUs A Function Annotation Server for Protein Structures

MarkUs A Function Annotation Server for Protein Structures. Markus Fischer, Donald Petrey, and Barry Honig Columbia University Center for Computational Biology and Bioinformatics NorthEast Structural Genomics Consortium. The importance of exploiting structure-function relationships. 571.

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MarkUs A Function Annotation Server for Protein Structures

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  1. MarkUs A Function Annotation Server for Protein Structures Markus Fischer, Donald Petrey, and Barry Honig Columbia University Center for Computational Biology and Bioinformatics NorthEast Structural Genomics Consortium

  2. The importance of exploiting structure-function relationships 571 PSI-BLAST Pfam Structure 5 1 146 304 115

  3. Not designed for hypothesis-driven queries Sequence analysis and structure analysis Static annotation pages List of neighbors List of target properties 1. 2. 3. AYWLMKSEPDEFSISDLQ LYWL-KSEPDLFSIT-LV IYFLFKT--DTFSIDTLK Prediction of function keywords How to identify false positives?

  4. Structural neighbors Sequence neighbors Query: 1 AYWLMKSEPDEFSISDLQ AYWL K+EPD FSI L+ Sbjct: 2 AYWLFKTEPDTFSIDTLK Skan Solvent accessible cavities Protein families and motifs InterPro Screen Residue conservation Electrostatic surface potentials ConSurf DelPhi Structure Analysis Sequence Analysis Integrate Structure Interactive Annotation Map Gene Ontology UniProt Ligand contacts ChEBI Ontology

  5. General introduction to the MarkUs interface Two example applications for the MarkUs server • Testing a hypothesis on protein function • Does NESG target 2eve interact with tRNA? • 2. Identification of a binding site • Where does sugar bind to VP8?

  6. Display cavities

  7. High Low Map residue conservation

  8. Negative Positive Map electrostatic potentials

  9. NESG target PsR62 (PDB 2eve) Structural neighbors YTH domains ASCH family potential mRNA binding domains connected to RNA metabolism PUA domains known to interact with tRNA Hypothesis: 2eve binds RNA

  10. How to identify RNA binding structural neighbors

  11. How to define a subset of structural neighbors

  12. Identify a structural neighbor of interest

  13. Superimpose a structural neighbor

  14. Negative Positive High Low Testing the hypothesis Residue conservation Electrostatic potentials NESG target 2eve PUA domain 1j2b

  15. How to identify a postulated sugar binding site? VP8* carbohydrate-recognizing domain From porcine CRW-8 rotavirus

  16. Identify sugar binding structural neighbors

  17. Identify sugar binding structural neighbors

  18. Identify sugar binding structural neighbors

  19. Identify sugar binding structural neighbors

  20. Identify sugar binding structural neighbors

  21. Define subset of sugar binding structural neighbors

  22. Define a subset of structural neighbors

  23. Identify sugar binding sites

  24. postulated 2nd binding site

  25. NESG software and databases Skyline High throughput modeling Pudge Refined models MarkUs http://luna.bioc.columbia.edu/honiglab/mark-us/ Skybase Models database (NESG, PDB) MarkUs Repository (NESG, PDB)

  26. NESG software and databases geWorkbench -> genomic data Skyline High throughput modeling Pudge Refined models MarkUs http://luna.bioc.columbia.edu/honiglab/mark-us/ Skybase Models database (NESG, PDB) MarkUs Repository (NESG, PDB)

  27. Conclusions • System for hypothesis-driven protein function annotation by comparison of local functional features • Interactive system guided by biological knowledge • Fast access to function annotations for protein structures

  28. Acknowledgements Thanks to the HonigLab and National Institutes of Health for financial support (grant U54-GM074958)

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