This is a proposal on the relationship of the structure of the thyroid hormone receptor to its response to hormone binding. The nuclear receptors for a super family of eukaryotic transcription factors that regulate gene expression in response to specific small-molecule ligands. The family includes the receptors for thyroid hormones (TR's), glucocorticoids, androgens, estrogens, retinoids and vitamin D. Naturally-occurring mutations in these receptors can participate in the pathogenesis of several human diseases, including cancers, syndromes resembling hormone deficiency, and other diseases In the proposed studies, the applicant will use the thyroid hormone receptor a a model receptor in a structural study to reveal the atomic-level causes of dysfunction in activation and repression of transcription. X-ray crystallography will be used to determine the structures of various mutant TR ligand-binding domains (LBD) bound to agonist ligands. The mutant receptors are selectively defective in aspects of receptor function; therefore, study of the dysfunctional molecules should allow dissection of those components of the TR LBD structure responsible for the receptor transcriptional activities. Structural information from these studies can be correlated to receptor properties measured in the biochemical lab and in some cases to the clinical features of affected patients. In this way, the studies are expected to contribute towards a general understanding of ligand-activated regulation of gene expression, and its role in the mechanism of certain diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053417-04
Application #
6381073
Study Section
Endocrinology Study Section (END)
Program Officer
Margolis, Ronald N
Project Start
1998-09-28
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
4
Fiscal Year
2001
Total Cost
$224,023
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Borngraeber, Sabine; Budny, Mary-Jane; Chiellini, Grazia et al. (2003) Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor. Proc Natl Acad Sci U S A 100:15358-63
Huber, B Russell; Sandler, Ben; West, Brian L et al. (2003) Two resistance to thyroid hormone mutants with impaired hormone binding. Mol Endocrinol 17:643-52
Marimuthu, Adhirai; Feng, Weijun; Tagami, Tetsuya et al. (2002) TR surfaces and conformations required to bind nuclear receptor corepressor. Mol Endocrinol 16:271-86
Wagner, R L; Huber, B R; Shiau, A K et al. (2001) Hormone selectivity in thyroid hormone receptors. Mol Endocrinol 15:398-410