Protein Structure Initiative Mission Statement. The long- range goal of the Protein Structure Initiative is to make the three- dimensional atomic-level structures of most proteins easily obtainable from knowledge of their corresponding DNA sequences.

Goals and Milestones SubCommittee Helen Berman David Eisenberg Wayne Hendrickson Andrzej Joachimiak Gaetano Montelione George Phillips Janna Wehrle Stephen Burley Ian Wilson PSI Goals and Milestones Document

Integration of PSI activities and organization of metrics of progress towards these goals is being done by the PSI Knowledge Base Using Goals and Milestones Document as a guide, with input from other PSI Steering Committee sub-committees

Primary Goals of PSI2 Large-scale Protein Structure Determination 3,000 Experimental Structures in PSI2 In addition to ~ 1300 in PSI1 4,300 total Large (BIG) and Very-large (Mega) Domain Families 70% effort Biomedical Targets 15% effort Community-nominated Targets 15% effort Broad structural coverage of protein sequences leveraged by homology modeling New Technologies and Infrastructure that accelerate the process and impact of 3D protein structure analysis Proactive Community Outreach

PSI provides 2 new 3D structures to PDB per day

Projected for Jul 1, 2010: 4646 structures

Representative Structures from BIG, Mega, Meta Families - 70% effort Sequence family U’ Sequence family U “Network Activity” “Modeling Families”

630 NESG Protein Structures Mar

Draft 1: 3 small MEGA families March 2007 OB - fold ( ) selected, cloned, soluble, purified, screened, in PDB ( PSI-1 / PSI-2 ) ( 3 / 10 ) 20 / 259 modeling families closed by NESG Tol - B ( ) selected, cloned, soluble, purified, screened, in PDB ( PSI-1 / PSI-2 ) ( 0 / 4 ) 14 / 355 modeling families closed by NESG FAD/NAD(P) – binding domain ( ) selected, cloned, soluble, purified, screened, in PDB ( PSI-1 / PSI-2 ) ( 1 / 5 ) 25 / 742 modeling families closed by NESG

Novel Leverage Sep Sept J. Liu, et al Nature Biotech 2007 PSI-BLAST E-value < 1e -10

Novel Leverage Sep Sept R. Nair et al J Struct Funct 2009 In PSI2 Yr 3, PSI provided 20% of Structures and ~60% of Novel Leverage of all US Structures Submitted to the PDB In recent years, PSI Structures have ~ fold higher leverage/structure than nonSG Structures (i.e. ~ 100 models / structure) Incremental coverage of UniProt since Jan 1, 2000 is 24% PSI has provided 25% (6% / 24%) of the new coverage of UniProt since Jan 1, 2000

Structural Coverage has advanced significantly in the past 10 Years PSI has made significant contributions … but there is still a lot left to do…

Protein Sequences Biological Function 3D Structure Deducing Biological Function from 3D Structure not a primary goal of PSI2 project

SG Can Enable Biology SG can target networks / biological processes while still addressing the PSI goals of structural coverage. SG technologies can be applied to prokaryotic, eukaryotic, human, and viral proteins. Structural similarity can provide clues to distant evolutionary relationships, and hypotheses regarding potential biochemical functions. Nature and locations of bound ligands can provide clues to biochemical function and mechanisms. PSI Knowledge Base and PSI Materials Repository provide information, protocols, and reagents which will provide the basis for traditional hypothesis-driven research projects.

Development of PSI - Biology Sep 2007PSI External Assessment Jul 2008Workshop on Homology Models for Biology Jul 2008PSI Directors Meeting Sep 2008PSI Directors White Paper Oct 2008Workshop on Visions for PSI3 Dec 2008Recommendations of PSI Steering Committee and Advisory Committee

Development of PSI - Biology Sep 2007PSI External Assessment Jul 2008Workshop on Homology Models for Biology Jul 2008PSI Directors Meeting: Visions for PSI3 Sep 2008PSI Directors White Paper Oct 2008Halloween Workshop: Visions for PSI3 Dec 2008Recommendations of PSI Steering Committee and Advisory Committee

PSI Directors White Paper

Opportunities for Structural Genomics Large Domain Families - BIG, MEGA Metagenomics: Structural Genomics of Ecological Niches Organisms or Organelles Systems Biology and Networks Pathways and Large Multiprotein Complexes Detailed structure / function / dynamic analysis across protein families

Metagenomics

Blue Nodes NESG Structures P53 p53 * * * * apoptosis TLR IL21(JAK)

Bacterial FeS Cluster Assembly Operons

Structure Electrostatic Surface Consurf Surface Electrostatic Surface Consurf Surface B.subtilis IscU (NMR) Kornhaber, Montelione H.influenzae IscU (NMR) Ramelot, Kennedy S.pyogenes IscU (X-ray) Liu, Kim E.coli SufE (X-ray) Kuzin, Hunt E.coli YgdK/SufE (NMR) Liu, Szyperski 180° Magenta - strongly conserved Cyan - less conserved Blue –positive charge Red – negative charge IscUs YgdK / SufE

Evolution of Structure and Function

Development of PSI - Biology Sep 2007PSI External Assessment Jul 2008Workshop on Homology Models for Biology Jul 2008PSI Directors Meeting Sep 2008PSI Directors White Paper Oct 2008Holloween Workshop on Visions for PSI3 Dec 2008Recommendations of PSI Steering Committee and Advisory Committee

Connecting with HTP Biology The Network organization of PSI2 (OMG) is a model of how to organize large-scale biology project Technology development, particularly for membrane proteins, should continue as a major component of PSI. Can Structural Genomics Synergize with other HTP Omics Programs? Our most abundant product is PROTEIN SAMPLES

Connecting with HTP Biology Large-scale Protein Interaction Networks HTP Biochemical Function Discovery HTP Gene Knock-out and Knock-in Experiments Large-scale Expression Array; Proteomics; Metabonomics Studies Large-scale RNA interference Studies Etc…

HTP Structure Determination Center HTP Structure Determination Center HTP Structure Determination Center HTP Structure Determination Center PSI3 - Biology Membrane Protein Center Membrane Protein Center Membrane Protein Center Membrane Protein Center Membrane Protein Center Membrane Protein Center Membrane Protein Center Membrane Protein Center HTP Enabled Structural Biology HTP Enabled Structural Biology HTP Enabled Structural Biology HTP Enabled Structural Biology HTP Enabled Structural Biology HTP Enabled Structural Biology HTP Enabled Structural Biology HTP Enabled Structural Biology

Centers for HTP Structure Determination Determination of Protein Structures using HTP Pipeline Cababilities Development of technology to improve the pipeline and to attack increasingly difficult proteins and complexes Bioinformatics analysis of potential targets, solved structures, and homology models Dissemination of Information and Materials via the Materials Repository and Knowledge Base Collaborative research with other members of the PSI Network to be established through PSI RFAs and PARs

Membrane Structure Production Centers Technology Development for Membrane Protein Targets Contribution in producing Network Targets

HTP Enabled Biology Close collaborations with HTP Structure Production Centers Rolling Application Process per year Subcontracts to Large-scale / Membrane Protein Centers for Structure Production Challenge - who will write these proposals??

Technology Development Central Task of Large-scale Centers Membrane Protein Centers are Technology- Development Centers PSI Program Announcements for Targeted Technology Development and Modeling Research Programs Enabling SG

HTP Structure Determination Center HTP Structure Determination Center HTP Structure Determination Center HTP Structure Determination Center PSI3 - Biology Integrated Network Integration via PSI KB and Materials Repository Membrane Protein Center Membrane Protein Center Membrane Protein Center Membrane Protein Center Membrane Protein Center Membrane Protein Center Membrane Protein Center Membrane Protein Center HTP Enabled Structural Biology HTP Enabled Structural Biology HTP Enabled Structural Biology HTP Enabled Structural Biology HTP Enabled Structural Biology HTP Enabled Structural Biology HTP Enabled Structural Biology HTP Enabled Structural Biology

PSI3 - Biology Concept Clearance: High-Throughput Structural Biology

PSI3 - Biology Concept Clearance: High-Throughput Structural Biology

PSI3 - Biology Concept Clearance: High-Throughput Structural Biology