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Plenary Speaker for the 2011 Oliver Smithies Nobel Lecture

TomSteitzimageDr. Thomas A. Steitz is Sterling Professor of Molecular Biophysics and Biochemistry and Professor of Chemistry at Yale University as well as an Investigator of the Howard Hughes Medical Institute. He received a B.A. degree in chemistry from Lawrence College in Appleton, Wisconsin, and a Ph.D. degree in molecular biology and biochemistry from Harvard, with William Lipscomb. After a postdoctoral year at Harvard, he moved to the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, to work as a Jane Coffin Childs fellow with David Blow. He next joined the Yale faculty, where he has remained, except for sabbatical work with Klaus Weber in Göttingen, Germany; Aaron Klug at Cambridge, England; John Abelson at the California Institute of Technology and Thomas Cech and Olke Uhlenbeck at the University of Colorado. He is a member of the U.S. National Academy of Sciences and the American Academy of Arts and Sciences. He has received the Pfizer prize from the American Chemical Society, the Rosenstiel Award for distinguished work in basic biomedical sciences, the AAAS Newcomb Cleveland Prize, the Keio Medical Science Prize, the Gairdner International Award and the 2009 Nobel Prize in Chemistry.

After a decade of successfully studying the structural basis of the glucose induced fit in hexokinase, research in the laboratory of Dr. Steitz has focused on obtaining insights into the molecular mechanisms by which the proteins and nucleic acids involved in the central dogma of molecular biology carry out gene expression from replication and recombination of the DNA genome to its transcription into mRNA followed by the various components associated with the translation of mRNA into protein. Not only are these processes fundamental to all life forms, but many of the macromolecules involved in these processes are known, or potential, targets for therapeutic drugs. In the 1980s, his lab established the structure to the catabolite gene activator protein and later its DNA complex, the structure of the first DNA polymerase Klenow fragment and the first structure of an aminoacyl tRNA synthetase bound to tRNA. His studies of T7 RNA polymerase captured in many of its functionally important states – initiation, intermediate, elongation – as well as stages of nucleotide incorporation and provide the most complete picture of RNA transcription by RNA polymerase. The recent structure of a replicative DNA polymerase from eubacteria showed it to be unrelated to that from eukaryotes, and thus a potential antibiotic target. The structure of the enzyme that copies the HIV viral RNA, HIV reverse transcriptase, into DNA was established complexed with the non-nucleotide inhibitor nevirapine and has facilitated the development of new non-nucleotide inhibitors. Perhaps the most significant insights have been derived from the atomic structure of the large ribosomal subunit. This structure proved that the ribosomal RNA is entirely responsible for catalyzing peptide bond formation and thus, the ribosome is a ribozyme (an enzyme made of RNA) and provided insights into how this mammoth RNA assembly is folded and functions as an enzyme. The large ribosomal subunit is probably the major target of antibiotics that are effective pharmaceuticals. The many structures of the large subunit complexed with various different antibiotics determined at Yale have identified numerous different antibiotic binding sites near the site of protein synthesis. This information has been enormously facilitating in the development of new antibiotics that will be effective against the rapidly increasing number of antibiotic resistant bacteria. Rib-X Pharmaceuticals, Inc. in New Haven has used this structural information to develop one compound that has successfully completed phase II clinical trials and a second that should enter clinical trials shortly.


“From the structure and function of the ribosome to new antibiotics”

TUESDAY, MARCH 8, 2011

3:00 – 5:00 p.m.

MBRB Auditorium G2204