This proposal is directed toward understanding how thyroid hormone receptors (TRs) recognize DNA and other proteins, and how thyroid hormone binds to the receptor and alters its regulatory activities. Additional studies will address the questions of what proteins interact with TRs and what the consequences of these interactions are, and what is the overall structure of TR and the effect of T3 on that structure.The proposed studies will explore large-scale expression and purification of the TRalpha ligand-binding domain (LBD) and full-length TRbeta, examine the mechanism of TR interactions with various DNAs and transcript ion factors such as retinoid x receptor (RXR), a rat liver RXR related factor, Pit-1, and a novel 120 kD factor. The investigators will study the functional consequences of these interactions, obtain crystals of the TRalpha LBD complexed with T3 and other ligands, the unliganded TRalpha LBD, and the full-length TRbeta. They will determine the three dimensional structure of the ligand bound TRalpha LBD at 2.8-3.0 angstrom resolution, and of the unbound TRalpha LBD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Endocrinology Study Section (END)
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Lou, Xiaohua; Toresson, Gudrun; Benod, Cindy et al. (2014) Structure of the retinoid X receptor ?-liver X receptor ? (RXR?-LXR?) heterodimer on DNA. Nat Struct Mol Biol 21:277-81
Figueira, A C M; Saidemberg, D M; Souza, P C T et al. (2011) Analysis of agonist and antagonist effects on thyroid hormone receptor conformation by hydrogen/deuterium exchange. Mol Endocrinol 25:15-31
Cunha Lima, Suzana T; Nguyen, Ngoc-Ha; Togashi, Marie et al. (2009) Differential effects of TR ligands on hormone dissociation rates: evidence for multiple ligand entry/exit pathways. J Steroid Biochem Mol Biol 117:125-31
Jouravel, Natalia; Sablin, Elena; Togashi, Marie et al. (2009) Molecular basis for dimer formation of TRbeta variant D355R. Proteins 75:111-7
Figueira, Ana Carolina Migliorini; Neto, Mario de Oliveira; Bernardes, Amanda et al. (2007) Low-resolution structures of thyroid hormone receptor dimers and tetramers in solution. Biochemistry 46:1273-83
Nguyen, Ngoc-Ha; Apriletti, James W; Baxter, John D et al. (2005) Hammett analysis of selective thyroid hormone receptor modulators reveals structural and electronic requirements for hormone antagonists. J Am Chem Soc 127:4599-608
Togashi, Marie; Borngraeber, Sabine; Sandler, Ben et al. (2005) Conformational adaptation of nuclear receptor ligand binding domains to agonists: potential for novel approaches to ligand design. J Steroid Biochem Mol Biol 93:127-37
Gloss, Bernd; Giannocco, Gisele; Swanson, Eric A et al. (2005) Different configurations of specific thyroid hormone response elements mediate opposite effects of thyroid hormone and GC-1 on gene expression. Endocrinology 146:4926-33
Nunes, F M; Aparicio, R; Santos, M A M et al. (2004) Crystallization and preliminary X-ray diffraction studies of isoform alpha1 of the human thyroid hormone receptor ligand-binding domain. Acta Crystallogr D Biol Crystallogr 60:1867-70
Sandler, Ben; Webb, Paul; Apriletti, James W et al. (2004) Thyroxine-thyroid hormone receptor interactions. J Biol Chem 279:55801-8

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