Fletterick, Robert - University of California, San Francisco - Department of Chemistry and Chemical Biology

研究领域

The foundations of molecular biology are built from molecular structures. Seeing these structures helps unravel the mysteries of life and makes biochemistry exciting. X-ray crystallography has shown how DNA is copied; proteins are manufactured from basic metabolites and a book of instructions and receptors receive signaling molecules and act to program new cell functions. Structural biology integrates chemistry and physiology. The Fletterick lab practices structural biology with purpose. That purpose is to learn about functions of systems in human biology and disease. We study function of critical proteins with X-ray crystallography, mutagenesis, cell, biochemical and biophysical assays, and chemistry. A major molecular focus of our laboratory is structure-function analyses of nuclear receptors including those for thyroid hormone, and androgen, and for the less well characterized receptors called LRH-1, SF-1, SHP and DAX-1. All of these receptors respond to hormonal signals and control processes in metabolism, biosynthesis and development; LRH-1 is critical in stem cell function and the steroid receptors control many aspects of biology from behavior to cancer. We try to develop structure-function relationships that will teach us how to control these receptors.

近期论文

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Yumoto F, Nguyen P, Sablin EP, Baxter JD, Webb P, Fletterick RJ. (2011) Structural Basis of Coactivation of Nuclear Receptor LRH-1 by beta-catenin. Proc Natl Acad Sci USA.109(1): 143-8. De Leon JT, Iwai A, Feau C, Garcia Y, Balsiger HA, Storer CL, Suro RM, Garza KM, Lee S, Kim YS, Chen Y, Ning YM, Riggs DL, Fletterick RJ, Guy RK, Trepel JB, Neckers LM, Cox MB. (2011) Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells. Proc Natl Acad Sci U S A. 108(29): 11878-83. Buz�n V, Carb� LR, Estruch SB, Fletterick RJ, Est�banez-Perpi�� E. (2011) A conserved surface on the ligand binding domain of nuclear receptors for allosteric control. Mol Cell Endocrinol. 348(2): 394-402. Benod C, Vinogradova MV, Jouravel N, Kim GE, Fletterick RJ, Sablin EP (2011) Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation. Proc. Natl. Acad. Sci. USA 108(41): 16927-16931. Hjelm R, Bennett Stone D, Fletterick RJ, and RA Mendelson. (2010) Decoration of microtubules in solution by the kinesin-14, Ncd. Acta Cryst. D66, 1218�1223 Wilbur JD, Hwang PK, Ybe JA, Lane M, Sellers BD, Jacobson MP, Fletterick RJ, Brodsky FM. (2010) Conformation switching of clathrin light chain regulates clathrin lattice assembly. Dev Cell. 18(5): 841-8. Pfaff SJ and Fletterick RJ. (2010) Hormone binding and co-regulator binding to the glucocorticoid receptor are allosterically coupled. J Biol Chem 285(20): 15256-67. Wilbur JD, Hwang PK, Brodsky FM, Fletterick RJ. (2010) Accommodation of structural rearrangements in the huntingtin-interaction protein 1 coiled-coil domain. Acta. Crystallogr. D. Biol Crystallogr. 66(Pt 3):314-8. Vinogradova MV, Malanina GG, Reddy AS, Fletterick RJ. (2009) Structure of the complex of a mitotic kinesin with its calcium binding regulator. Proc Natl Acad Sci U S A. 106(20): 8175-9. Sablin EP, Blind RD, Krylova IN, Ingraham JG, Cai F, Williams JD, Fletterick RJ and HA Ingraham (2009) Structure of SF-1 bound by different phospholipids: Evidence for regulatory ligands. Mol Endocrinol. 23(1): 25-34. Sablin EP, Woods A, Krylova IN, Ingraham HA and RJ Fletterick. (2008) The Structure of corepressor DAX-1 bound to its target nuclear receptor LRH-1. Proc. Natl.Acad. Sci. 2105(47): 18390-5. Cruz LA, Estébanez-Perpiñá E, Pfaff S, Borngraeber S, Bao N, Blethrow J, Fletterick RJ, England PM. (2008) 6-Azido-7-nitro-1,4-dihydroquinoxaline-2,3-dione (ANQX) forms an irreversible bond to the active site of the GluR2 AMPA Receptor. J Med Chem. 51(18): 5856-60. Wilbur JD, Chen CY, Manalo V, Hwang PK, Fletterick RJ, Brodsky FM. (2008) Actin binding by Hip1 (huntingtin-interacting protein 1) and Hip1R (Hip1-related protein) is regulated by clathrin light chain. J Biol Chem. 283(47): 32870-9. Jouravel N, Sablin E, Fletterick RJ. (2008) Molecular basis for dimer formation of TRb variant D355R. PROTEINS: Structure, Function & Bioinformatics 75(1): 111-117. Vinogradova M, Malanina G, Reddy V, Reddy A and RJ Fletterick. (2008) Structural dynamics of the microtubule binding and regulatory elements in the kinesin-like calmodulin binding protein. J Structural Biology 163(1): 76-83. Jouravel N, Sablin E, Arnold LA, Guy RK and RJ Fletterick. (2007) Interaction between the androgen receptor and a segment of its corepressor SHP. Acta Cryst. D63, 1198–1200 Arnold LA, Kosinski A, Estébanez-Perpiñá E., Fletterick RJ, and RK Guy. (2007) Inhibitors of the interaction of a thyroid hormone receptor and coactivators: Preliminary structure-activity relationships. J Medicinal Chemistry 50(22): 5269-80. Estébanez-Perpiñá, E., Jouravel, N.and Fletterick, R.J. Developing therapeutic agents for androgen-independent prostate cancer. Expert Opinion on Drug Discovery, Volume 2, Number 10, October 2007, pp. 1341-1355(15) Publisher: Informa Healthcare Estébanez-Perpiñá, E., Jouravel, N., Arnold, L.A., Togashi, M., Mar, E., Sablin, E., Nguyen, P., R. Baxter, J.D., Webb, P., Guy, R. K. and Fletterick, R.J. (2007) Structural insight into the mode of action of a direct inhibitor of coregulator binding to the thyroid hormone receptor. Molecular Endocrinology (12): 2919-28.