Protein Structure Initiative Mission Statement. The long- range goal of the Protein Structure...

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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 BermanDavid Eisenberg

Wayne Hendrickson Andrzej JoachimiakGaetano Montelione

George Phillips Janna Wehrle

Stephen Burley Ian Wilson

PSI Goals and Milestones Document

Integration of PSI activitiesand 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 Determination3,000 Experimental Structures in PSI2

In addition to ~ 1300 in PSI1 4,300 totalLarge (BIG) and Very-large (Mega) Domain Families 70% effortBiomedical Targets 15% effortCommunity-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”

“ModelingFamilies”

630 NESG Protein Structures

Mar 1 2009

Draft 1: 3 small MEGA familiesMarch 2007

OB - fold ( 2.40.50.140 )

selected, cloned, soluble, purified, screened, in PDB ( PSI-1 / PSI-2 )

401 147 96 33 93 13 ( 3 / 10 )20 / 259 modeling families closed by NESG

Tol - B ( 2.120.10.30 )

FAD/NAD(P) – binding domain ( 3.50.50.60 )

Novel Leverage Sep 1 2000 - Sept 15 2008

J. Liu, et al Nature Biotech 2007

PSI-BLAST

E-value < 1e-10

Novel Leverage Sep 1 2000 - Sept 15 2008

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 ~ 6.5 - 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 2007 PSI External Assessment

Jul 2008 Workshop on Homology Models for Biology

Jul 2008 PSI Directors Meeting

Sep 2008 PSI Directors White Paper

Oct 2008 Workshop on Visions for PSI3

Dec 2008 Recommendations of PSISteering Committee andAdvisory Committee

Jul 2008 PSI Directors Meeting: Visions for PSI3

Oct 2008 Halloween Workshop: Visions for PSI3

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

apoptosisTLR

IL21(JAK)

Bacterial FeS Cluster Assembly Operons

StructureElectrostatic

SurfaceConsurfSurface

ElectrostaticSurface

ConsurfSurface

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

Magenta - strongly conserved

Cyan - less conserved

Blue –positive charge

Red – negative charge

YgdK / SufE

Evolution of Structure and Function

Jul 2008 PSI Directors Meeting

Oct 2008 Holloween Workshop on Visions for PSI3

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…

HTPStructure

DeterminationCenter

HTPStructure

DeterminationCenter

HTPStructure

DeterminationCenter

HTPStructure

DeterminationCenter

PSI3 - Biology

Membrane ProteinCenter

HTP Enabled StructuralBiology

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 3 - 4 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

HTPStructure

DeterminationCenter

HTPStructure

DeterminationCenter

HTPStructure

DeterminationCenter

HTPStructure

DeterminationCenter

PSI3 - Biology

Integrated Network

Integration via PSI KB and Materials Repository

Membrane ProteinCenter

HTP Enabled StructuralBiology

PSI3 - Biology

http://www.nigms.nih.gov/Initiatives/PSI

Concept Clearance: High-Throughput Structural Biology

PSI3 - Biology

http://www.nigms.nih.gov/Initiatives/PSI

PSI3 - Biology

Protein Structure Initiative Mission Statement. The long- range goal of the Protein Structure...

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