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Protein informatics & structure-based analysis

Protein informatics & structure-based analysis. Ming-Jing Hwang ( 黃明經 ) 中研院生醫所 N121 (02) 2789-9033 http://gln.ibms.sinica.edu.tw/. Protein Informatics: Objective.

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Protein informatics & structure-based analysis

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  1. Protein informatics & structure-based analysis Ming-Jing Hwang (黃明經) 中研院生醫所 N121 (02) 2789-9033 http://gln.ibms.sinica.edu.tw/

  2. Protein Informatics: Objective • Given a protein query (sequence or structure), extract, by in silico methods, as much information/knowledge as possible about this protein.

  3. Protein Informatics: Approaches • Homology search/knowledge transferring • Non-homology-based

  4. Protein Informatics: contents • Primary Databases: sequence & structure • Secondary (derived) Databases: motifs, domains, families, functional sites, etc. • Tools and Webservers

  5. NAR database collection

  6. Protein databases

  7. NAR database Distribution of NAR Molecular Biology Database Collection Web site.

  8. Bioinformatics links directory

  9. Primary sequence databases

  10. UniProtKB

  11. Short sequence motifs

  12. Block logos Residues that contribute to one of the blocks returned by BLOCKS database after submission of the PI3-kinase p100a sequence. (A) 4 homologues (B) 31 homologues.

  13. Domains and families

  14. Integrated databases

  15. Ncbi http://www.ncbi.nlm.nih.gov/Sitemap/ResourceGuide.html

  16. Primary structure database

  17. Protein Data Bank (PDB) http://www.rcsb.org/pdb/home/home.do

  18. Structure Summary

  19. Structure Information (PDBsum)

  20. Viewing Molecules

  21. Structure Visualization Tools • Interactive viewers KiNG (http://kinemage.biochem.duke.edu/software/king.php) Jmol (http://jmol.sourceforge.net/) WebMol (http://www.cmpharm.ucsf.edu/cgi-bin/webmol.pl) • Plugin viewers RasMol (http://www.bernstein-plus-sons.com/software/rasmol/) Swiss PDB Viewer (http://au.expasy.org/spdbv/) • Molecular graphics software Cn3D (http://www.ncbi.nlm.nih.gov/Structure/CN3D/cn3d.shtml) PyMOL (http://pymol.sourceforge.net/)

  22. RasMol plugin viewer

  23. Other Structure Databases

  24. Analyzing Structure-Function Relationship Understanding Bioinformatics (Chap. 14) Marketa Zvelebil & Jeremy O. Baum

  25. Why structure-function relationship? • Function is determined by structure (similar functions share structural fold). • Structure can provide more detailed info about function (e.g. binding sites). • With structure, many more analyses can be performed. • Reminder: however, examples exist of proteins with different functions having the same fold, and vice versa.

  26. Str. alignment Structure-based alignment When sequence fails to reveal evolutionary kinship, structure often can.

  27. a/b protein; parallel b sheet (b-a-b motifs) active site at C-terminal end of the barrel highly common for enzymes (>900 structures in CATH) diverse functions (divergent vs. convergent evolution) The TIM barrel fold

  28. TIM barrel is one of heavily used functional units Gerstein & Hegyi, 1998

  29. TIM-barrel proteins have diverse functions Non-enzyme

  30. Similar fold but not fun. Two immunoglobulin-like b-sandwich folds with distinct functions

  31. Different types (structures) of phosphopeptide-binding proteins SH2 (Src homology domain) PTB (phospho-tyrosine binding domain) PH (pleckstrin homology)

  32. CATH: a structural classification database

  33. Domain cutting: Cbl as an example (Domain as a unit for structure comparison)

  34. Blast (seq. comp.) fails to predict a SH2 domain

  35. Top CE hits are SH2-containing proteins

  36. (interact with phosphotyrosine) Structural alignments reveal conserved functional sites (VAST results)

  37. DALI finds Grb10 SH2 (DALI ignores seq order)

  38. FATCAT aligns Cbl with an OB fold – after a twist

  39. P53 has many interacting partners How to find binding sites? Two types: (1) large areas on surface (2) pockets or clefts

  40. Binding architecture of RNA polymerase II

  41. The interaction regions of survivin : using surface properties (charges, etc.) (sulfate/phosphate binding)

  42. Binding site characteristics: patch of conserved hydrophobic or polar residues; mainly b-sheets or long loops; clusters of either hydrophobic or aromatic residues at the interface p53-ASPP2 ProMate: an automatic interface-prediction program

  43. Partner presently unknown ASPP2 or DNA PPI-PRED predicts three PPI sites (in red) for p53.

  44. Identification of p53 binding sites using ConSurf (PSI-BLAST + ClustalW)

  45. Calculation of solvent-accessible surface can identify clefts or holes, which are potential binding sites. SURFNET, Pocket-Finder, and Q-SiteFinder are three programs that can do this.

  46. DHFR Lignad binding-site programs (Q-SiteFinder and Pocket-Finder) find probable cavities where ligands can bind.

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