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Çağdaş DAĞ

STRUCTURAL GENOMICS. Çağdaş DAĞ. What is Structural Genomics ?. Is the process of high- throughtput determination of 3-D structures of Biological macromolecules. What is the Goal of Structural Genomics ?.

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Çağdaş DAĞ

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  1. STRUCTURAL GENOMICS Çağdaş DAĞ

  2. What is Structural Genomics ? Is the process of high-throughtput determination of 3-D structures of Biological macromolecules What is the Goal of Structural Genomics ? Provision of enough structural templates to facilitate homology modeling of most proteins. Structural elucidation of complete biological pathway To determine new protein folds To determine the functions of unknown proteins • to develop improved methods that will result in high-throughput biology and protein structure determination

  3. What can we learn from structure ? The structure will reveal the fold of the protein The structure may reveal evolutionary links between proteins lacking sequence similarity The structure will reveal the active site The structure may reveal the function of the protein

  4. Overview Structural Genomics

  5. Target Selection • Complete organisms; • thermophilic, mesophilic or halophilic • eukaryotic or prokaryotic • HUMAN DISEASE • Targets in this area of structural genomics are G-protein coupled receptors, ion channels and kinases etc. • The development of techniques to allow over-expression, purification and crystallization of these targets is required and in progress

  6. Cloning, Expression and Purification • Develop technologies necessary for large-scale initiatives • develop high-throughput (HTP) cloning • develop high-throughput expression • develop high-throughput purification

  7. STRUCTURE DETERMINATION NMR Spectroscopy CRYSTALLOGRAPHY Protein <20 kDa NMR N15 C13Label Protein (>20kDa) Protein-Protein Interactions Aggregated, Unfolded Folded Insoluble Soluble Co-Expression Protein-Protein Interactions Expression Purification Limited Proteolysis Structure Crystal Trials Stable Domain Co-Expression

  8. STRUCTURAL GENOMIC CENTERS The first phase of the Protein Structure Initiative (PSI-1) lasted from June 2000 until September 2005, and had a budget of $270 million funded primarily by NIGMS The second phase of the Protein Structure Initiative (PSI-2) lasted from July 2005 to June 2010 PSI-2 had a five-year budget of $325 million provided by NIGMS BIGS - Bacterial Targets at IGS-CNRS, France BSGC - Berkeley Structural Genomics Center, USA CESG - Center for Eukaryotic Structural Genomics, USA ISPC - Israel Structural Proteomics Center, Isreal JCSG - Joint Center for Structural Genomics, USA MCSG - The Midwest Center for Structural Genomics, USA, UK, Canada NESG - Northeast Structural Genomics Consortium, USA NYSGRC - New York SGXRC - New York Structural Genomics Research Consortium, USA OPPF - Oxford Protein Production Facility, UK PSF - Protein Structure Factory, Germany RIKEN - RIKEN Structural Genomics Initiative, Japan S2F - Structure 2 Function Project SECSG - SouthEast Collaboratory for Structural Genomics, USA SGPP - Structural Genomics of Pathogenic Protozoa Consortium, USA SPEX Db - (BSGI) - Montreal-Kingston Bacterial Structural Genomics Initiative, Canada SPINE - Structural Proteomics in Europe, EU TB - Mycobacterium tuberculosis (TB) Structural Genomics Consortium, 70 labs from 12 countries XMTB - Mycobacterium Tuberculosis Structural Proteomics Project, Germany

  9. Determinated Protein Structures PSI grant period LSC ALL-PSI PSI-2 grant year 2005 390 427 PSI-2 grant year 2006 620 700 PSI-2 grant year 2007 682 718 PSI-2 grant year 2008 796 818 PSI-2 grant year 2009 822 879 PSI-2 grant extension 217 244 PSI-2 total depositions 3527 3786 PSI-3 grant year 2010 280 283 PSI-3 total depositions 377 381 PSI-1 + PSI-2 + PSI-3 4804 5583

  10. The Northeast Structural Genomics (NESG) consortium Production stage NESG targets cloned   23,695 Expression tested   22,159 Expressed (E > 0)   16,888 Expressed-Soluble (S > 0) 12,453 Expressed-Soluble (ES >= 9) 9,946 Fermented   7,271 Purified (>= 0.5 mg yield) 4,848 HSQC spectra recorded 2,597 "Good" HSQC spectra 1,353 HTP crystal screening 2,522 Crystal hit   1,295 X-Ray structures   547 NMR structures   452 Total structures   958 Human proteins Production stage NESGtargets cloned   5,479 Expression tested 5,046 Expressed (E > 0) 3,986 Expressed-Soluble (S > 0) 2,599 Expressed-Soluble (ES >= 9) 2,051 Fermented   1,097 Purified (>= 0.5 mg yield) 813 HSQC spectra recorded 422 "Good" HSQC spectra 235 HTP crystal screening 320 Crystal hit   130 X-Ray structures   35 NMR structures   66 Total structures   93

  11. The Midwest Center for Structural Genomics (MCSG)

  12. The Center for Eukaryotic Structural Genomics-National Magnetic Resonance Facility-Madison • University of Wisconsin-Madison

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