Robert J. Fletterick, PhD
Professor Emeritus, Departments of Biochemistry/Biophysics and Cellular/Molecular Pharmacology, UCSF
My lab is focused on structure function studies of nuclear receptors and transcription control proteins in stem cells. My lab uses biochemical and biophysical methods to evaluate protein complexes. Among the technologies employed are surface plasmon resonance, X-ray crystallography, and differential scanning fluorescence. Mutagenesis and cell assays are employed to gauge functional effects of mutagenesis to evaluate the hypotheses linking structure to function. We determined the first three-dimensional structure for any nuclear receptor and published papers on the thyroid hormone receptor, androgen receptor, and glucocorticoid receptor, as well as on LRH-1, SF-1, and Dax-1 receptors, and developed bait-affinity expression for making the first complex of a nuclear receptor with its corepressor. Research on androgen receptor interactions with peptides and small molecules helped define the specificity of the AF2 site and led to the discovery of a new protein binding site on the androgen receptor hormone binding domain.
My lab is known for determining structures of important protein molecules and assemblies, and relating structures to the mechanisms of function of the macromolecules. Many of the papers from the lab are recognized by experts as useful contributions to the field. Early papers from my lab were mostly on learning about allosteric control of enzyme catalysis. Using glycogen phosphorylase as the target, we determined the structure at high resolution for the phosphorylated dimer, normally active but inhibited by an allosteric effector. At about 200,000 molecular weight, this protein was the largest with known structure for about ten years. We also embraced recombinant DNA methods early. Ours was the first lab to clone all isozymes for any human protein. Our muscle cDNA library was used by others to clone challenging targets, including the first Ca ATPase. With expertise in cloning technologies, we were positioned to compare the regulation of glycogen phosphorylases in evolution from yeast to human. Recognition of my work on allostery was the basis for election to the National Academy of Sciences. Recently, our lab has focused on learning more about mechanisms of transcription factors, especially nuclear receptors. This focus led us to publish our first paper in cancer biology that identifies a potential target for treating pancreatic cancer.
Marietta College, Marietta, Ohio, B.S., 1965, Chemistry
Cornell University, Ithaca, New York, Ph.D., 1970, Physical Chemistry
Yale University, New Haven, Connecticut, Department of Molecular Biophysics and Biochemistry, Laboratory of Prof. Thomas Steitz, Postdoctoral Fellow, 1970-1971, X-ray Crystallography
Yale University, New Haven, Connecticut, Department of Biophysics and Biochemistry, Postdoctoral Fellow, 1971-1973, X-ray Crystallography