Janet L. Smith

Margaret J. Hunter Collegiate Professor of Life Sciences and
Professor of Biological Chemistry

Ph.D., University of Wisconsin-Madison
Postdoctoral Fellow, Naval Research Laboratory

Research Focus: Protein Structure and Function using X-ray Crystallography

Phone: 734.615.9564
E-mail: janetsmith@umich.edu
Fax: 734.763.6492

Our research focuses on protein structure and function, using X-ray crystallography as a structural tool. We have a long-standing focus on "complex" enzymes that catalyze multi-step reactions in multiple active sites. The major projects in the lab aim to understand how the multiple catalytic modules of “assembly line” polyketide synthases work together to produce specific antibiotic products. The catalytic modules of these remarkable enzymes are four- or five-domain proteins, each domain having a catalytic or carrier function. An intricate set of conformational changes accomplishes the signaling and channeling necessary to achieve tightly coupled catalysis. We have examined full module structures by collaboration with cryo-EM experts, docking interactions that insure pathway fidelity, and enzyme domains that catalyze novel chemical reactions. A second research area is the replication complex of flaviviruses, human pathogens that cause West Nile and dengue fever and for which there is neither vaccine nor effective antiviral drug. Recent work is focused on a virulence factor with multiple functions in the viral life cycle. In the study of these biological systems, we employ modern high-throughput methods to investigate which proteins, protein domains or protein complexes are most suited to structural study, and we apply the latest tools of micro-crystallography with synchrotron radiation to address challenging structural problems.

The three projects are excellent examples of how transient protein structures and conformational change are used to control enzyme activity. For the viral replicase and polyketide synthase projects, we employ new high-throughput methods to investigate which proteins, protein domains or protein complexes are most suited to structural study.

Smith Research Group



Fellow of the American Association for the Advancement of Science
Herbert Newby McCoy Award - Purdue University


Representative Publications

  1. Giraldes, J.W., Akey, D.L., Kittendorf, J.D., Sherman, D.H., Smith, J.L. and Fecik, R.A., "Tools for Enzyme Engineering: Design, Synthesis, Inactivation, and Crystal Structures of Polyketide-based Affinity Labels with Pikromycin Thioesterase", Nature Chem. Biol., Epub ahead of print.

  2. Akey, D.L., Kittendorf, J.D., Giraldes, J.W., Fecik, R.A., Sherman, D.H. and Smith, J.L., "Structural Basis for Macrolactonization by the Pikromycin Thioesterase", Nature Chem. Biol., Epub ahead of print.

  3. Cramer, W.A., Yan, J., Zhang, H., Kurisu, G. and Smith, J.L., "Structure of the cytochrome b6f complex: new prosthetic groups, Q-space, and the 'hors d'oeuvres hypothesis' for assembly of the complex", Photosynthesis Res., 2005, 85, 133.

  4. Cramer, W.A., Zhang, H., Yan, J., Kurisu, G. and Smith, J.L., "Trans-membrane traffic in the cytochrome b6f complex", Ann. Rev. Biochem., 2006, 75, 769.

  5. Chander, P., Halbig, M., Miller, J.K., Fields, C.J., Bonner, H.K.S., Switzer, R.L. and Smith, J.L., "Structure of the nucleotide complex of PyrR, the pyr attenuation protein from Bacillus calfolyticus, suggests dual regulation by pyrimidine and purine nucleotides", J. Bacteriol., 2005, 187, 1773.

  6. Wu, J., Bera, A.K., Kuhn, R.J. and Smith, J.L., "Structure of flavivirus helicase: implications for catalytic activity, protein interactions and proteolytic processing", J. Virology, 2005, 79, 10268.

  7. Dahms, T.E.S., Sainz, G., Giroux, E.L., Caperelli, C.A. and Smith, J.L., "The apo and ternary-complex structures of a chemotherapeutic target: human glycinamide ribonucleotide transformylase", Biochem., 2005, 44, 9841.