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Wells, James
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Small molecule allosteric inhibitor bound at
the dimer interface of caspase-1 (J. Scheer).
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| Location: | 1700 4th Street 503A | | Phone Number: | 415-514-4498 | | FAX Number: | 415-514-4507 | | Email: | jim.wells@ucsf.edu | | Lab Groups: | Faculty |
| Research Statement | | Dr. Wells received a B.A. degree in biochemistry from the University of California, Berkeley, and a Ph.D. degree in biochemistry from Washington State University. His postdoctoral studies were done at Stanford University Medical School, Department of Biochemistry. Dr. Wells was the founding member of the Protein Engineering Department at Genentech, Inc where he worked for 16 years. His research focused on designing new functional properties into enzymes and hormones and developing new technologies for engineering proteins. In 1998, Dr. Wells founded Sunesis Pharmaceuticals where he served as President and Chief Scientific Officer and developed a novel fragment discovery technology known as disulfide trapping or Tethering. In 2005, Dr. Wells joined UCSF as the Harry W. and Diana Hind Distinguished Professor in Pharmaceutical Sciences. He is a joint Professor in the Departments of Cellular & Molecular Pharmacology, and Pharmaceutical Chemistry.
We are interested in the discovery and design of small molecules that trigger or modulate cellular processes in inflammation and cancer. Our research spans the multiple disciplines of biophysics, cell biology, molecular biology, biochemistry and chemistry. We are interested in the allosteric “circuitry” in proteins, i.e., how two distant functional sites communicate through a protein. In particular, we are focused on the signaling circuitry in pathways involved in cell death and cellular inflammation. We are developing specific cell active enzyme inhibitors or activators by using a novel disulfide trapping technology which allows us to target specific sites on proteins and determine their role in driving cellular signaling processes. This technology allows us to trap allosteric states so that they may be studied by biophysical and mutational means. We are using this approach to determine the role of specific inflammatory caspases via selective inhibitors and study activation of proteins in proliferation and apoptotic pathways via allosteric activators. This approach will identify “orphan allosteric sites’ which may have natural binding partners and pose new targets for drug discovery. In addition, we are developing methods for tagging N-termini of proteins using engineered enzymes so we can follow proteolytic cascades especially those in apoptosis and cellular inflammation.
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Publications | | Buck, E. and Wells, J.A. (2005) "Disulfide Trapping to Localize Small Molecule Agonists and Antagonists for the Complement 5a Receptor", Proc. Natl. Acad. Sci. USA 102, 2719-2724.
Hardy, J.A., Lam, J., Nguyen, J.T., O'Brien, T. and Wells, J.A. (2004) "Discovery of an Allosteric Site in Caspases", Proc. Natl. Acad. Sci., USA 101, 12461-12466.
Nguyen, J. and Wells, J.A. (2003) "Direct Activation of the Apoptosis Machinery as a Mechanism to Target Cancer Cells", Proc. Natl. Acad. Sci. USA 100, 7533-7538.
Thanos, C.D., Randal, M., and Wells, J.A. (2003) "Potent Small-molecule Binding to a Dynamic Hot-spot on IL-2", J. Am. Chem. Soc., 125, 15280-15281.
DeLano, W.L., Ultsch, M.H., De Vos, A.M. and Wells, J.A. (2000) "Convergent Solutions to Binding at a Protein:Protein Interface", Science 287, 1279-1284.
Erlanson, D.A. Braisted, A.C., Raphael, D.R., Randal, M., Stroud, R.M., Gordon, E.M. and Wells, J.A. (2000) "Site-Directed Ligand Discovery", Proc. Natl. Acad. Sci. USA 97, 9367-9372. |
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