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Molecular Biology of Cancer: Content, Data and Tools for Biology Curriculum Development

Molecular Biology of Cancer: Content, Data and Tools for Biology Curriculum Development. Jeff Milton. Protein Data Bank. Worldwide consortium: EBI, RCSB PDB, PDBj Protein Data Bank Japan, Osaka University Research Collaboratory for Structural Bioinformatics, UCSD & Rutgers

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Molecular Biology of Cancer: Content, Data and Tools for Biology Curriculum Development

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  1. Molecular Biology of Cancer: Content, Data and Tools for Biology Curriculum Development Protein Data Bank, SDSC Jeff Milton

  2. Protein Data Bank • Worldwide consortium: EBI, RCSB PDB, PDBj • Protein Data Bank Japan, Osaka University • Research Collaboratory for Structural Bioinformatics, UCSD & Rutgers • European Bioinformatics Institute, Cambridge UK • As of Tuesday Feb 21, 2006 there are 35,246 Structures • Protein, DNA, RNA, Protein complexes • Methods: X-ray Crystallography (29,800) , NMR (5254), Electron Microscopy and other methods (192) • Data In: ~200 / week • PDB ID required for structure publication • Structural Genomics Initiative, NIH • Reduce the cost and increase the rate of structure determination • Discover protein function • Research biomedical problems and better therapeutics Protein Data Bank, SDSC

  3. Education at the Protein Data Bank, SDSC • Molecular Biology of Cancer • Compelling Animations by Drew Berry • Interviews with field experts, Vega Sciences Productions • Dissemination: www.pdb.org. 100,000 unique hits a month from ~150 different countries around the world • Software for technology enhanced learning • Molecular viewers, sequence viewers integrated with data • Molecule of the Month • Web content that highlights functional traits of important molecules. Written by David Goodsell, TSRI • CalIT2 Virtual Reality CAVE • Virtual Cave environment for enhanced visualization of protein structures. Directed by Jurgen Shulze, CalIT2 Protein Data Bank, SDSC

  4. Molecular Biology of Cancer Hanahan D, Weinberg RA.Department of Biochemistry, Hormone Research Institute, University of California at San Francisco, 94143, USA. Protein Data Bank, SDSC

  5. “The Hallmarks of Cancer” • Evading apoptosis • Self-sufficiency in growth signals • Insensitivity to anti-growth signals • Tissue invasion & metastasis • Limitless replication potential • Sustained angiogenesis Hanahan D, Weinberg RA.Department of Biochemistry, Hormone Research Institute, University of California at San Francisco, 94143, USA. Protein Data Bank, SDSC

  6. Example: Cell proliferation and self-sustained growth How do cells grow and divide? How do cells learn self-sustained growth? What causes a cell to divide? • Start with synthesis of the EGF Receptor protein • Central Dogma • Localization to the cell membrane • Trans-membrane protein • EGF and EGF receptor binding  signal into the cell • EGF-EGFR crystal structure • Cascade leads to a protein called RAS • Molecular Switch • “ON”  cell proliferation What is different about cancer cells? • e.g. cancer cells require little growth factors Protein Data Bank, SDSC

  7. EGF binds to EGFR • 2 EGFRs activate a series of proteins that lead to activation of RAS • RAS is activated to the “on” position • Cell Division • RAS is turned “off” A simple view of the pathway Cell enters irreversibly into “S” phase Protein Data Bank, SDSC

  8. Mutations lead to self sufficient growth signals • Mutations in gene regulation • Over-expression of EGF receptor molecules • Cell creates growth factors that it can also bind to. • Too many receptors cause hypersensitivity to ambient signals • Mutations in protein structure • EGF receptor may be deployed to the membrane with a mutation that causes it to be stuck in the active state. • RAS or RasGAP may be mutated, preventing RAS from shutting off Protein Data Bank, SDSC

  9. Rational Drug Design: Iressa • Lung Cancer • Small molecule that inhibits the auto-stimulatory action of a mutated form of the EGF receptor. • Doesn’t work on over-expression of the wild type EGF receptor Protein Data Bank, SDSC

  10. Real Structural Data Integration: 3D structure from the PDB highlights the activation mechanism down to the atomic detail. E.G. How Ras is turned off. This structure shows the molecular switch GTP  GDP What are the consequences of mutations that lead to weak interactions between these protein structures? PDBID: 1WQ1, Scheffzek, K., Ahmadian, M.R., Kabsch, W., Wiesmuller, L., Lautwein, A., Schmitz, F., Wittinghofer, A. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science v277 pp.333-338 , 1997 Protein Data Bank, SDSC

  11. Connections to related diseases Neurofibromatoses: autosomal dominant Neurofibroma is an enzyme that performs the same function as Ras-GAP. i.e. it turns RAS “off” in certain types of neurons. A known germline mutation in NF1 gene causes failure of this mechanism and an accumulation of RAS in the “on” position. This leads to benign tumors in dermal, brain and spine. This usually leads to series developmental problems, blindness. This debilitating disease affects 1 in 3,000 males and females of all races and ethnic groups. 1NF1, Scheffzek, K.,  Ahmadian, M.R., Wiesmuller, L.,  Kabsch, W.,  Stege, P., Schmitz, F.,  Wittinghofer, A. Structural analysis of the GAP-related domain from neurofibromin and its implications. EMBO J. v17 pp.4313-4327 , 1998 Protein Data Bank, SDSC

  12. Example Tools for curriculum development ImageMap Query Interface. An ImageMap generator that links schematics to a query at PDB, GenBank, etc. Example: 22 TGF-alpha growth factors and 18 Ras signaling proteins Sequence Viewer and Molecular Viewer for highlighting point mutations Virtual Lab from the ChemCollective for Biochemistry activities: Develop experiments to determine the binding constant of RasGAP Protein Data Bank, SDSC

  13. http://www.pdb.org Protein Data Bank, SDSC

  14. Integrated software tools for enhanced visualization and data mining. Enhanced searching capabilities: This will be expanded to include searching on structures used in animations. Integrated visualization tools Protein Data Bank, SDSC

  15. What is the Framework for curriculum development and dissemination Documentary design: Interleave fundamental biological mechanisms with popular science concepts Integrate visual animations and imagery of important biological processes Integrate real experimental data with the biology and highlight directions in discovery and therapeutics. Build tools to help curriculum developers integrate PDB Data with content and publish to the PDB web site according to relevant standards. Protein Data Bank, SDSC

  16. NSF, Informal Science Education (ISE) • Designed to increase interest, engagement and understanding of science, technology, engineering, and mathematics. • Not curriculum development • Framework for curriculum development • Capture important biological processes and provide tools for activity development • Teachers don’t have time • Activities archived and disseminated according to national science standards. • Assessment? • http://nsf.gov/pubs/2006/nsf06520/nsf06520.htm Protein Data Bank, SDSC

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