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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK041842-04A2
Application #
2141942
Study Section
Endocrinology Study Section (END)
Project Start
1989-08-01
Project End
1996-11-30
Budget Start
1993-12-06
Budget End
1994-11-30
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Lou, Xiaohua; Toresson, Gudrun; Benod, Cindy et al. (2014) Structure of the retinoid X receptor α-liver X receptor β (RXRα-LXRβ) 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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