Steitz, Thomas A.

Sterling Professor of Molecular Biophysics and Biochemistry
Yale University

Thomas Steitz

Thomas A. Steitz, a faculty member since 1970, was appointed the Sterling Professor of Molecular Biophysics and Biochemistry. He is internationally known for his work in X-ray crystallography, which he uses to study the molecular structure of proteins and nucleic acids. Steitzís lab was the first to produce close-up pictures of transfer RNA as its genetic code was being translated into the basic components of life. In 1992, he determined the three-dimensional structure of a key protein called reverse transcriptase, which is responsible for transcribing the virusís genetic material.

Thomas A. Steitz

Eugene Higgins Professor of Molecular Biophysics and Biochemistry, and Chemistry
Ph.D. Harvard University 1966; Jane Coffin Childs Fellow, MRC Laboratory of Molecular Biology, Cambridge, England, 1967-70; joined Yale Faculty 1970; Macy Fellow, Göttengen, Germany, 1976-77; Fairchild Scholar, Caltech 1984-85; visiting professor, University of Colorado, Boulder 1992-93; member, National Academy of Sciences, 1990; member, American Academy of Arts and Sciences, 1990. Pfizer Award in Enzyme Chemistry, 1980; Investigator, Howard Hughes Medical Institute.


Structure and mechanism of protein complexes with DNA and RNA


Our major interests are in the molecular mechanisms by which the proteins and nucleic acids involved in DNA replication, transcription, translation and genetic recombination achieve their biological function. Virtually all aspects of the maintenance, rearrangement and expression of information stored in the genome involve interactions between proteins and nucleic acids. While in the past structural studies have focused on simple complexes between a protein and its specific nucleic acid substrate, future directions will increasingly target the more complex macromolecular assemblies that are the functional machines in these processes.

Among the questions being asked about these protein complexes with nucleic acids are: How do the sequence specific DNA or RNA binding proteins recognize the particular DNA or RNA sequence to which they bind? What common structural principles exist among proteins that interact with nucleic acids? How do the template directed polymerases assure high fidelity in the copying of templates? How do aminoacyl-tRNA synthetases discriminate among tRNA molecules and charge only their cognate tRNA? What can we learn about the principles of RNA structure and how do RNA enzymes work? How are two duplex DNAs of homologous sequence aligned and how are the DNAs rearranged upon recombination? How do the proteins that work in concert with polymerases alter the polymerase activities (e.g. transcription factors with RNA polymerase and replication accessory proteins with DNA polymerase)? How is the initiation of DNA replication achieved and regulated? Answers to these and related questions are being sought using X-ray crystal structure determination of appropriate macromolecular complexes, testing of hypothesis using site directed mutageneses and biochemical studies to relate structure to function.

Our recent structures of Taq DNA polymerase and its complex with primer-template are providing insights into the mechanism of the polymerase reaction and the fidelity of DNA copying. The structure of the single-stranded DNA binding protein with DNA gives a glimpse into replication accessing proteins. The structure of resolvase with 34 b.p. of DNA shows the wonderful versatility of specific DNA recognition and bending, but the mechanism of site specific recombination awaits the structure of higher order complexes. Structure of Gln-tRNA synthetase with mutated tRNA molecules is providing insight into specific RNA recognition. The structure of the E. coli lac repressor core and that of T7 RNA polymerase complexed with a transcriptional repressor (which is in progress) give insights into transcription regulation.

The 2.9 Å crystal structure of HIV reverse transcriptase complexed with an anti-AIDS drug and more recently its structure complexed with an RNA pseudo-knot inhibitor as well as future structures with an RNA template and tRNA primer are the starting points for rational design of anti-AIDS drugs.


Smerdon, S.J., Jäger, J., Wang, J., Kohlstadet, L.A., Chirino, A.J., Friedman, J.M., Beese, L.S. and Rice, P.A. (1994). Two Polymerases: HIV Reverse Transcriptase and the Klenow Fragment of E. coli DNA Polymerase I. Proc. Natl. Acad. Sci. USA 91: 3911-3915.

Joyce, C.A. and Steitz, T.A. (1994). Function and Structure Relationships in DNA Polymerases. Annu. Rev. Biochemistry 62: 777-822.

Rould, M.A., Perona, J.J. and Steitz, T.A. (1991). Structure Basis of Anticodon Loop Discrimination by Glutaminyl-tRNA Synthetase. Nature 352, 213-218.

Yang, W. and Steitz, T.A. (1995). Crystal Structure of the Site Specific Recombinase Resolvase Complexed with a 34 Base Pair Cleavage Site. Cell, in press.

Friedman, A.M., Fischmann, T.O. and Steitz, T.A. (1995). Unprecedented Quaternary Structure of E. coli lac Repressor Core Tetramer: Implications for DNA Looping. Science, in press.

Endowed professorships have long helped Yale to attract and retain some of the brightest minds and best teachers in academia. Several longtime faculty members were recently honored with the Universityís highest faculty chair, the Sterling Professorship.

The Sterling Professorships represent one of the continuing benefits from the 1918 bequest by John W. Sterling B.A. 1864. His gift enabled Yale to construct many of its most prominent campus structures, among them Sterling Memorial Library, Sterling Law Buildings, Sterling Divinity Quadrangle, and Sterling Hall of Medicine. It also set aside funds to endow the 28 Sterling Professorships.