Ligand search and data mining of Structural Genomics structures

1. Ligand search and data mining of Structural Genomics structures Abhinav Kumar, Herbert Axelrod, Ashley Deacon Structure Determination Core, Joint Center for Structural Genomics (JCSG), Stanford Synchrotron Radiation Laboratory, Menlo Park, CA, USA Distribution of Ligands The Joint Center for Structural Genomics (JCSG) The JCSG (www.jcsg.org) is one of the four large-scale structural genomics centers funded by NIGMS as part of the production phase of the Protein Structure Initiative (PSI). More than 2600 structures have been deposited into the PDB by the PSI centers as of 2007, of which the JCSG has contributed over 500 structures. Although the major part of JCSG's resources is dedicated to protein structure determination, we are also making efforts to disseminate information gained from these structures to a larger community of researchers. Here we report the development of a web-based data mining engine (smb.slac.stanford.edu/public/jcsg/cgi/jcsg_ligand_check.pl) that queries all of the PSI structures based on a variety of search criteria. The main objective is to extract ligands, biological or otherwise, bound to the structures, and to explore them further with a number of associated links. In addition, the structures can be queried by a host of other criteria, such as target names, PDB IDs, PFAM family names, structure descriptions, organisms, and PSI centers. Preliminary analysis indicates that 1515 of these PSI structures have some type of bound ligand, metal or solvent molecules, and 262 of these structures contain 136 unique biological ligands. Interestingly, several of these ligands had not been previously identified in structures in the PDB. In addition, 21 different co-factors have been observed in 210 structures. Co-factors Ligands FMN 11 10 9 1 2 3 8 4 7 6 NDP PLP FS4 MPO GAL Metal Ions Non-metal Ions Buffers Precipitants The Role of the Structure Determination Core in the JCSG Examples of Search Queries • Screen Crystals and Collect Data • Automatically Process Data • Refine and Evaluate Structures • Disseminate Information* • Publish • Web based Tools • TOPSPAN (www.topsan.org) • Ligand Search (smb.slac.stanford.edu/public/jcsg/cgi/jcsg_ligand_check.pl) Autoindex Integrate Scale Solve Trace JCSG Ligand Search * in collaboration with BIC 5 A typical Search Result Unique PSI Ligands Unique Ligands 10-Oxohexadecanoic acid (OHA) bound to the structure of Ferredoxin-like Protein (JCVI_PEP_1096682647733) from an environmental metagenome (Unidentified Marine Microbe) (2OD6) (R)-2-Hydroxy-3-Sulfopropanoic acid (3SL) bound to the structure of putative 2-phosphosulfolactatetitle 2 phosphatase from Clostridium Acetobutylicum (1VR0) Indole-3-Carboxaldehyde (I3A) bound to the structure of tellurite resistance protein of cog3793 (zp_00109916.1) from Nostoc Punctiforme PCC 73102 (2OU3) FB8805A (2Q9K) Unknown protein Unknown Ligands (UNL) FK9436A (2OH1) Acetyltransferase Gnat family Search Results (35 hits) Ligands bound to JCSG new folds Exploring Binding Modes of Ligands N Target PDB PFAM Accession Description Organism Ligands PSI 9 out of 26 new fold structures from JCSG have bound ligands, which identify their active sites and give some clues to function. Often the ligands are modeled as UNL, because their precise identity is unknown. There are over 340 structures in PDB with the co-factor Flavin Mononucleotide (FMN) bound to the protein 1 FB10607B 2r6v PF01613 NP_142786.1 Crystal Structure of FMN-binding Protein (NP_142786.1) from Pyrococcus Horikoshii at 1.35 Å resolution Pyrococcus Horikoshii Ot3 EDOFMNNCA JCSG The binding poses of FMN display considerable variations due to the torsional flexibility in the molecule. PF01243 (Pyridox_oxidase ) PF01613 (Flavin reductase like) PF01180 (DHOdehase ) PF00881 (Nitroreductase) 2 FH7614A 2ig6 PF01243 NP_349178.1 Crystal Structure of NIMC/NIMA Family Protein (NP_349178.1) from Clostridium Acetobutylicum at 1.80 Å resolution Clostridium Acetobutylicum EDOFMNSO4 UNL JCSG 3 FJ9446A 2ou5 PF01243 YP_508196.1 Crystal Structure of Pyridoxamine 5'-phosphate Oxidase- Related FMN-binding (YP_508196.1) From Jannaschia Sp. Ccs1 at 1.60 Å resolution Jannaschia Sp. Ccs1 FMNGOLSO4 JCSG However, unique binding poses can be observed in proteins belonging to specific PFAM families. . … … … … … … … … 34 SGT98480 1q45 PF00724 NP_178662.1 12-0xo-Phytodienoate Reductase Isoform 3 Arabidopsis Thaliana FMN CESG Number of Structures PF00724 (Oxidored_FMN ) PF00258 (Flavodoxin _1) PF01070 (FMN-dependent dehydrogenase ) PFAM PSI Non-PSI Total 1VRM 2ICH 35 TB0885A 1vp8 PF08981 NP_068944.1 Crystal Structure of Hypothetical Protein (NP_068944.1) from Archaeoglobus Fulgidus at 1.30 Å resolution Archaeoglobus Fulgidus Dsm 4304 FMN UNL JCSG PF01243 7 14 21 PF00881 9 8 17 1KQ4 1VJL 1VR0 PF00258 3 13 16 PF00724 2 8 10 Ligand Visualization Links PF01613 2 7 9 HIC-Up: ACYADPAMPBRCACLEDOFMNGLCGOLIODMGNCANIOROP33PO4SO4 PF01180 1 8 9 1VQ0 1VKM 1VK9 1VKY Ligand Depot: ACYADPAMPBRCACLEDOFMNGLCGOLIODMGNCANIOROP33PO4SO4 PF01070 0 8 8 GNF & TSRI (Crystallomics Core) Scott Lesley Mark Knuth Dennis Carlton Thomas Clayton Kevin D. Murphy Christina Trout Marc Deller Daniel McMullan Heath Klock Polat Abdubek Claire Acosta Linda M. Columbus Julie Feuerhelm Joanna C. Hale Thamara Janaratne Hope Johnson Linda Okach Edward Nigoghossian Sebastian Sudek Aprilfawn White Bernhard Geierstanger Glen Spraggon Ylva Elias Sanjay Agarwalla Charlene Cho Bi-Ying Yeh Anna Grzechnik Jessica Canseco Mimmi Brown UCSD & Burnham (Bioinformatics Core) John Wooley Adam Godzik Slawomir Grzechnik Lukasz Jaroszewski Dana Weekes Lian Duan Sri Krishna Subramanian Natasha Sefcovic Piotr Kozbial Andrew Morse Prasad Burra Tamara Astakhova Josie Alaoen Cindy Cook TSRI (Admin Core) Ian Wilson Marc Elsliger Gye Won Han David Marciano Henry Tien Xiaoping Dai Lisa van Veen TSRI (NMR Core) Kurt Wüthrich Reto Horst Maggie Johnson Amaranth Chatterjee Michael Geralt Wojtek Augustyniak Pedro Serrano Bill Pedrini William Placzek Stanford /SSRL (Structure Determination Core) Keith Hodgson Ashley Deacon Mitchell Miller Debanu Das Hsiu-Ju (Jessica) Chiu Kevin Jin Christopher RifeQingping Xu Silvya Oommachen Scott Talafuse Henry van den Bedem Ronald Reyes Christine Trame Scientific Advisory Board Sir Tom Blundell Robert Stroud Univ. Cambridge Center for Structure of Membrane Proteins Homme Hellinga Membrane Protein Expression Center Duke University Medical CenterUC San Francisco James Naismith James Paulson The Scottish Structural Proteomics facilityConsortium for Functional Glycomics Univ. St. Andrews The Scripps Research Institute Soichi Wakatsuki Todd Yeates Photon Factory, KEK, Japan UCLA-DOE Inst. for Genomics and Proteomics James Wells UC San Francisco The JCSG is supported by the NIH Protein Structure Initiative (PSI) Grant U54 GM074898 from NIGMS (www.nigms.nih.gov). Portions of this research were carried out at the Stanford Synchrotron Radiation Laboratory (SSRL). The SSRL is a national user facility operated by Stanford University on behalf of the U.S. Department of Energy, Office of Basic Energy Sciences. The SSRL Structural Molecular Biology Program is supported by the Department of Energy, Office of Biological and Environmental Research, and by the NIH.