Speakers

Thomas A. Steitz, Ph.D.

“From Understanding the Ribosome Structure and Function to Designing New Antibiotics”

Tuesday, Sept. 26, 2006, 11:45 a.m. – 12:15 p.m.

Schiciano Auditorium, Fitzpatrick CIEMAS Building

Abstract:

Over two million patients a year are infected by antibiotic resistant bacteria in U.S. hospitals each year and over 90,000 die. The large subunit of the ribosome is perhaps the major target of antibiotics. The atomic resolution structure of the large ribosomal subunit and its complexes with substrate mimics as well as antibiotics have allowed us to not only understand how this ribonuclear protein machine is able to catalyze peptide bond formation utilizing only its RNA components, but also understand how antibiotics inhibit the ribosome function. Studies of mutant ribosomal subunits bound to antibiotics provide insights into some mechanisms of antibiotic resistance. These structural studies have provided the foundation for the design of new antibiotics effective against all resistant bacteria by Rib-X Pharmaceuticals, Inc., which now has compounds in clinical trials.

Biography:

Thomas Steitz received his B.A. in Chemistry from Lawrence College in Appleton, Wisc., in 1962. He then pursued his Ph.D. studies at Harvard University in the laboratory of William Lipscomb, receiving his degree in Biochemistry and Molecular Biology in 1966. Dr. Steitz's doctoral studies on the crystal structure of carboxypeptidase A initiated his career in structural biochemistry in which he has used X-ray crystallography as his primary tool. He subsequently pursued postdoctoral studies of alpha-chymotrypsin with David Blow at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England.

In 1970 Dr. Steitz was appointed an Assistant Professor of Molecular Biophysics and Biochemistry, Yale University, where he is currently the Sterling Professor of Molecular Biophysics and Biochemistry, Professor of Chemistry and Investigator in the Howard Hughes Medical Institute. Dr. Steitz has also pursued sabbatical studies with Klaus Weber in Göttingen, Germany; with Aaron Klug in Cambridge, England; with John Abelson at the California Institute of Technology; and with Tom Cech and Olke Uhlenbeck in Boulder, Colorado.

During the past three decades, Dr. Steitz has used X-ray crystallography to determine the structures of proteins and nucleic acids, particularly those involved in gene expression and recombination, with a consistent focus on their biological function. His studies on yeast hexokinase with and without bound glucose demonstrated that substrate binding induced a large conformational change, closing the deep cleft in the enzyme.

Virtually all aspects of nucleic acid metabolism have come under his scrutiny -- replication, transcription, recombination, and protein synthesis. The structures of lac repressor core and the catabolite gene activator protein plus its complex with DNA have led to molecular insights into gene activation and repression. Insights into the structural basis of transcription initiation and elongation phases as well as its regulation were derived from the six structures of T7 RNA polymerase complexes with a transcriptional repressor, with an open promoter DNA, with a promoter DNA and a three nucleotide RNA transcript and with 30 base-pairs of DNA and a 17 nucleotide RNA transcript.

Clues concerning the mechanism and fidelity of DNA copying have come from the structures of DNA polymerases complexed with DNA, and the reverse transcriptase from HIV complexed with an anti-AIDS drug. The crystal structures of Gln-tRNA synthetase bound to tRNAGln as well as Ile-tRNA synthetase bound to tRNAIle have answered many questions concerning the mechanisms by which the genetic code is accurately translated. Also the laboratory has provided insights into the details of genetic recombination through studying the structures of E. coli recA and a site-specific recombination protein, resolvase, bound to DNA caught in the act of recombination.

Most recently, the first atomic level insights into the structure and function of the ribosome have come from crystal structure analysis of the 50S ribosomal subunit and structures with bound substrates and antibiotics, have yielded insights into the mechanism of peptide bond formation and its inhibition. The structures of these antibiotic complexes are leading to the design on new antibiotics, now in phase I trials, by Rib-X Pharmaceuticals, Inc., co-founded by Dr. Steitz.

Dr. Steitz is a member of the National Academy of Sciences and the American Academy of Arts and Sciences and is the recipient of the 1980 Pfizer Award in Enzyme Chemistry of the American Chemical Society, the 2001 Rosenstiel Award for Distinguished Work in Basic Medical Research, the 2001 AAAS Newcomb Cleveland Prize and the 2002 Lawrence University Lucia R. Briggs Distinguished Achievement Award.