Cytoplasmic Tyrosine Kinase Structure, Function, and Chemical Biology
My research program applies an interdisciplinary approach to a broad range of questions surrounding the roles of cytoplasmic protein-tyrosine kinase signaling pathways in cancer and AIDS. Specific research areas related to the MBSB graduate program include structure-function relationships governing the activity and signaling of multidomain kinases of the Src, Abl, Tec, and Fes families. We have worked closely with biophysicists for many years to better understand the structures and dynamics of these unique kinase systems. For example, in collaboration with John Engen of Northeastern University, we have used hydrogen-deuterium exchange mass spectrometry to study dynamic changes in kinase structures that result from interactions with effector proteins and small molecules. In addition, working with Stefan Knapp of Oxford University and the Structural Genomics Consortium, we determined the X-ray crystal structure of the c-Fes tyrosine kinase in complex with a novel inhibitor that represents a drug lead for acute myelogenous leukemia. Here at Pitt, we are working on crystal structures of the HIV Nef virulence factor in complex with Src and Tec-family kinases as well as novel small molecule inhibitors discovered by our group. Structural biology will continue to play a key role in the hit-to-lead development of these Nef inhibitors as new therapeutics for HIV disease. Our laboratory offers training opportunities for students with an interest in the application of biophysical methods to better understand protein kinases as well as their interactions with binding partners and small molecules.
Education
Ph.D., University of Pennsylvania, Philadelphia, PA
Postdoctoral Training
National Cancer Institute, NIH, Bethesda, MA
Department of Microbiology and Molecular Genetics
University of Pittsburgh
Suite 523, Bridgeside Point II
450 Technology Drive
Pittsburgh, PA 15219
Phone: (412) 648-8106
Fax: (412) 624-8997
E-mail: tsmithga@pitt.edu
Website: http://www.mmg.pitt.edu/person/thomas-e-smithgall
