Planning for the Protein Structure Initiative National Advisory General Medical Sciences Council September 2003

1. NIGMS Protein Structure Initiative Planning for the Protein Structure Initiative National Advisory General Medical Sciences Council September 2003

2. NIGMS Protein Structure Initiative Structural Genomics • Begins with genetic information • Discovery-driven projects • Unique, non-redundant protein structures • Large-scale, organized, multidisciplinary projects • Major investments in infrastructure • Lengthy scaling-up periods • International effort

3. NIGMS Protein Structure Initiative Structural Genomics Basics • Target strategy: systematic sampling of protein sequence families to search for unique protein structures • Experimental determination of unique protein structures in high throughput operation • Computational modeling of structures of sequence family homologs

4. NIGMS Protein Structure Initiative Protein Structure Initiative (PSI)Long-Range Goal To make the three-dimensional atomic level structures of most proteins easily available from knowledge of their corresponding DNA sequences

5. NIGMS Protein Structure Initiative Expected PSI Benefits • Structure provides information on function and will aid in the design of experiments • Development of better therapeutic targets from comparisons of protein structures from: • Pathogens vs. hosts • Diseased vs. normal tissues

6. NIGMS Protein Structure Initiative PSI Benefits (Continued) • Collection of structures will address key biochemical and biophysical problems • Protein folding, prediction, folds, evolution, etc. • Benefits to biologists • Technology developments • Structural biology facilities • Availability of reagents and materials • Experimental outcome data on protein production and crystallization

7. NIGMS Protein Structure Initiative PSI Pilot Phase • 5-year pilot phase, September, 2000 • Pilot phase Goals • Development of high throughput structure genomics pipeline • Pilots for testing all facets and strategies • PSI target selection policy • Representatives of protein sequence families • Rational search for unique, non-redundant protein structures • Public listing of all targets and progress toward structure determination

8. NIGMS Protein Structure Initiative PSI Pilot Research Centers • Seven research centers funded in FY2000 • Two additional research centers funded in FY2001 • Co-funding by NIAID for two of the nine research centers • Many subprojects

9. PSI Pilot Research Centers p UK UK, Japan, Israel

10. PSI Advisory Committee NIGMS Protein Structure Initiative • Brian Matthews (Chair), University of Oregon • David Davies, NIDDK, NIH • Chris Dobson, Cambridge University • Tony Kossiakoff, University of Chicago • Ed Lattman, Johns Hopkins University • Rowena Matthews, University of Michigan • Frank Prendergast, Mayo Clinic • Chris Sander, Sloan-Kettering Cancer Center • Gerhard Wagner, Harvard University • Cathy Wu, Georgetown University Medical School

11. NIGMS Protein Structure Initiative PSI Advisory Committee Progress Review (March 2003) Comments from the Chair’s letter: • “…very impressed and highly encouraged by the progress” • “In some cases, well-planned, highly efficient pipelines have been developed…” • “…100 or more structure determinations per year, very substantial progress by some of the groups .....” • “…novel technologies and approaches that could have a large impact…” • “…membrane proteins…difficult and challenging…complexes…some of the centers are beginning to address these…”

12. NIGMS Protein Structure Initiative PSI Pilot Phase -- Lessons Learned • Structural genomics pipelines can be constructed and scaled-up • High throughput operation works for many proteins • Genomic approach works for structures • Bottlenecks remain for some proteins • A coordinated, 5-year target selection policy must be developed • Homology modeling methods need improvement

13. NIGMS Protein Structure Initiative PSI-2 Production Phase (2005) • Interacting network for high throughput protein structure determination with three components • Large-scale centers for protein structure production of selected targets • Specialized centers for technology development leading to high throughput structure determination of difficult proteins • Specialized centers for protein structures relevant to disease (other NIH Institutes and Centers) • Included in NIH Structural Biology Roadmapplans

14. NIGMS Protein Structure Initiative PSI-2 Production Phase Program changes (following May 2003 Council) • Refinement of the PSI goals statement • To ensure completion of the production phase within the 5-year period, staff and members of the PSI Advisory Committee are developing target selection policy, milestones, and project end-point

15. NIGMS Protein Structure Initiative PSI-2 Production PhaseProgram changes (continued) • Specialized centers for technology and methodology development: greater specificity • Structural genomics projects focused on completion of protein structures in an organism: deleted • Specialized centers for protein structures relevant to disease: supported by other NIH institutes and centers

16. NIGMS Protein Structure Initiative PSI-2 Large-scale Centers • High throughput structure output (200 or more unique structures per year for each center) • Target selection based on protein family representatives • Quantitative 5-year goals with milestones • High throughput operation of all tasks of the structural genomics pipeline • Provisions for sharing facilities with the scientific community

17. NIGMS Protein Structure Initiative PSI-2 Large-scaleCenters (continued) • Activities to promote research training • Activities to promote the participation of underrepresented minority researchers and/or students in structural biology research • 3 to 5 awards expected • Maximum requested budgets $8M dc • Supported by NIGMS

18. NIGMS Protein Structure Initiative PSI-2 Large-scale Centers Target selection • Representatives of large protein families • Quantitative goals • 5-year plan • Milestones • Project end-point

19. NIGMS Protein Structure Initiative PSI-2 Large-scale Centers Target selection • Dramatically increase the number of families with known structures • Increase unique structures to ~8,000 • Increase structural coverage of sequenced genes • Concentrate on large sequence families • Increase structural information on sequenced genes to 70% • Consider biological impact • Requires 8,000 to 10,000 unique experimental structures

20. NIGMS Protein Structure Initiative PSI-2 Large-scale Centers Target selection planning • Target Selection Workshop, Nov. 2003 • Research center staff, experts, PSI Advisory Committee (public) • Meeting of PSI Advisory Committee and PIs (public), Dec. 2003 • Meeting of PSI Advisory Committee (closed), Dec. 2003

21. NIGMS Protein Structure Initiative PSI-2 Large-scale Centers Homology Modeling • High Accuracy Comparative Modeling Workshop, Oct. 2003 • Identify roadblocks to significantly improve the accuracy of comparative modeling • Co-chairs, Rich Friesner and John Moult

22. NIGMS Protein Structure Initiative PSI-2 Specialized CentersMethodology and Technology Development • Leading toward high throughput operation for difficult proteins & problems • Membrane proteins • Higher eukaryote proteins, especially human • Other major bottlenecks to high throughput • Could focus on a subset of structural genomics tasks • Maximum requested budgets $3M dc • 3 to 6 awards • Supported by NIGMS and other NIH institutes and centers

23. NIGMS Protein Structure Initiative PSI-2 Specialized CentersStructures for Function and Disease • Protein structures from pathogens and from tissues and organ systems related to disease • Member of the PSI network • Maximum requested budgets $3M dc • May be supported by other NIH institutes and centers (not NIGMS)

24. NIGMS Protein Structure Initiative PSI-2 Planning • Development of PSI-2 RFAs, Jan 2004 • PSI-2 applications reviewed by Council, May 2005 • PSI Pilots (FY 2003-4) • $65 million total cost annual budget • PSI-2 Production (FY2005) • $75 million total cost annual budget

25. NIGMS Protein Structure Initiative Research Centers Structures determined 01 77* 02 109 03 217 TOTAL 403 * 31 started prior to award

26. NIGMS Protein Structure Initiative PSI Structure Statistics2002-2003 • Unique structures (30% seq. ID) PSI 70% PDB 10% • New folds PSI 12% PDB 3%

27. NIGMS Protein Structure Initiative Average total cost per structure PSI Pilot phase 01 $650 K (7 centers) 02 $400 K (9 centers) 03 $240 K 04 ? 05 $100 K (goal) PSI-2 Production phase 06-10 $50 K (goal) Comparison ~$250-300 K

28. NIGMS Protein Structure Initiative http://www.nigms.nih.gov/psi/