Research: Decoding the internal workings of the protein assemblies that catalyze complex biological functions remains the imperative of structural molecular biology. Accomplishing this goal will require study of ever-larger molecular assemblies chosen to answer specific biochemical questions. The biological systems that I have selected for initial study are the nucleo-protein assemblies that are formed at the sites of the initiation of DNA replication. Accurate replication of DNA is mediated by multi-protein assemblies that initiate DNA synthesis, elongate daughter strands, and assure the integrity of the catalyzed chemical reactions. We will use X-ray crystallography to determine the structure of selected functionally relevant assemblies with the goal of understanding biochemical data present in these systems. Structure determinations will be followed by functional studies of designed variants of these assemblies to test models of biochemical function. While the primary goal of this work will be to decipher biological function, studies of these assemblies are expected to provide the added benefit of making available much-needed targets for structure-based design of antibiotics and anti-cancer therapeutics.
Selected Publications: Jeruzalmi, D. and Steitz, T. A. (1997) Use of organic cosmotropic solutes to crystallize flexible proteins: application to T7 RNA polymerase and its complex with the inhibitor T7 lysozyme. J Mol Biol, 274, 748-756. Jeruzalmi, D. and Steitz, T. A. (1998) Structure of T7 RNA polymerase complexed to the transcriptional inhibitor T7 lysozyme. EMBO J, 17, 4101-4113. Cheetham, G. M. T., Jeruzalmi, D. and Steitz, T. A. (1999) Structural basis for initiation of transcription provided by an RNA polymerase-promoter complex. Nature, 399, 80-83. Zhao, Y., Jeruzalmi, D. Moarefi, I., Lasken, R., Leighton, L. and Kuriyan, J. (1999) Crystal structure of an archaebacterial DNA polymerase. Structure, 7, 1189-1199. Moarefi, I., Jeruzalmi, D., Turner, J., and Kuriyan, J. (2000) Crystal Structure of the DNA Polymerase Processivity Factor of T4 Bacteriophage. J Mol Biol, 274, 748-756. Jeruzalmi, D., Yurieva, O., Zhao, Y., Young, M., Stewart, J., Hingorani, M., O’Donnell, M., and Kuriyan, J. (2001) Mechanism of Processivity Clamp Opening by the Delta Subunit Wrench of the Clamp Loader Complex of E. coli DNA Polymerase III. Cell, 106, 417-428. Jeruzalmi, D., O’Donnell, M., and Kuriyan, J. (2001) Crystal Structure of the Processivity Clamp Loader Gamma (g) Complex of E. coli DNA Polymerase III. Cell, 106, 429-441. Bruck I., Yuzhakov A., Yurieva O., Jeruzalmi D., Skangalis M., Kuriyan J., O'Donnell M. (2002) Analysis of a multicomponent thermostable DNA polymerase III replicase from an extreme thermophile. J Biol Chem 277:17334-48 O’Donnell, M., Jeruzalmi, D., and Kuriyan, J., (2001) Structure of a Clamp Loader and Implications for Replisome Structure and RFC Function. Curr. Biol. 11:R935-46. Jeruzalmi, D., O’Donnell, M., and Kuriyan, J. (2002) Clamp Loaders and Sliding Clamps. Curr Opin Struct Biol, 12:217-24. Jeruzalmi, D., (2004) Chromosomal DNA replication on a protein "chip". Structure, 12:2100-2. Jeruzalmi, D., (2005) The Opened Processivity Clamp Slides into View. Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):14939-40. |
