Why Structure?

2. Proteins • do most of the work in the body • are shaped to get their job done • Protein structure • Offers clues about the role it plays in the body • May hold the key to developing new medicines and diagnostic procedures Why Structure? From Alisa Zapp Machalek, The Structures of Life

3. Myoglobin Hemoglobin CrystalStructures Lysozyme Ribonuclease Myoglobin: Kendrew, Bodo, Dintzis, Parrish, Wyckoff, Phillips, Nature 181 662-666, 1958.Hemoglobin: Perutz, Proc. R. Soc. A265, 161-187,1962. Lysozyme: Blake, Koenig, Mair, North, Phillips, Sarma, Nature 206 757, 1965. Ribonuclease: Kartha, Bello, Harker, Nature 213, 862-865 1967. Wyckoff, Hardman, Allewell, Inagami, Johnson, Richards. J. Biol. Chem. 242, 3753-3757, 1967.

4. How do people use these structures if they did not personally determine them? “The History of the PDB”

5. Protein crystallography begins to take off • Emerging interest in protein folding • Use of computer graphics to represent structure 1960’s 1962 Nobel Prize awarded for the first three-dimensional protein structures – myoglobin and hemoglobin (determined by M. F. Perutz and J. C. Kendrew) Hemoglobin

6. Grass roots community efforts to archive data • Protein crystallographers discuss how to archive data • June 1971 • Cold Spring Harbor meeting brings groups together (Cold Spring Harbor Symposia on Quantitative Biology, vol. XXXVI, 1972.) • October 1971 • PDB is announced in Nature New Biology (7 structures; vol 233, 1971, page 223) • 1975 • PDB receives first funding from NSF (~32 structures) 1970’s

7. CHAD Nature New Biology

8. Technology takes off • molecular biology, instrumentation, computer hardware and software • Structural biology is able to focus on medical problems • Community efforts to promote data sharing • IUCr guidelines requiring data deposition in the PDB are published 1980’s Structure of the first membrane-bound protein (a photosynthetic reaction centre) by J. Deisenhofer, R. Huber and H. Michel (Nobel Prize in Chemistry, 1988)

9. Number of structures increases exponentially • Complexity of structures increases • New databases begin to emerge • More structures determined by cryo- electron microscopy • Plans for structural genomics emerge • User community for the PDB expands dramatically 1990’s RCSB awarded contract for the PDB

10. Continued growth in structure studies • Structural genomics takes off • RCSB PDB contract renewed 2000’s 2bus Kurt Wüthrich, who determined the first first three-dimensional protein structure by NMR spectroscopy with coworkers (proteinase IIa inhibitor from bull seminal plasma) was awarded the Nobel Prize in Chemistry in 2002

12. Identify all the approximately 30,000 genes in human DNA • Determine the sequences of the 3 billion chemical base pairs that make up human DNA • Store this information in databases • Improve tools for data analysis • Transfer related technologies to the private sector • Address the ethical, legal, and social issues (ELSI) that may arise from the project Human Genome Project Image credit: U.S. Department of Energy Human Genome Program, http://www.ornl.gov/hgmis. Text: http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml

13. Structural Genomics “The next step beyond the human genome project” From the NIH Request for Proposals for Structure Genomics Centers: “These studies should lead to an understanding of structure/function relationships and the ability to obtain structural models of all proteins identified by genomics. This project will require the determination of a large number of protein structures in a high-throughput mode.”

14. Hurricane Floyd, Sept 1999 IUCr Aug 1999 January 1999 IUCr 1999 PDB Dedication Dec 1999

15. IUCr Aug 2002 November 2002 January 2002 IUCr Aug 2002