Journal
MOLECULAR ENDOCRINOLOGY
Volume 15, Issue 3, Pages 398-410Publisher
OXFORD UNIV PRESS INC
DOI: 10.1210/me.15.3.398
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- NIDDK NIH HHS [DK-53417, DK-41842] Funding Source: Medline
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Separate genes encode thyroid hormone receptor subtypes TR alpha (NR1A1) and TR beta (NR1A2). Products from each of these contribute to hormone action, but the subtypes differ in tissue distribution and physiological response. Compounds that discriminate between these subtypes in vivo may be useful in treating important medical problems such as obesity and hypercholesterolemia. We previously determined the crystal structure of the rat (r) TR alpha ligand-binding domain (LBD). In the present study, we determined the crystal structure of the rTR alpha LED in a complex with an additional ligand, Triac (3,5, 3'-triiodothyroacetic acid), and two crystal structures of the human (h) TR beta receptor LBD in a complex with either Triac or a TR beta -selective compound, GC-1 [3,5-dimethyl-4-(4'-hydroy-3'-isopropylbenzyl)-phenoxy acetic acid]. The rTR alpha and hTR beta LBDs show close structural similarity. However, the hTR beta structures extend into the DNA-binding domain and allow definition of a structural hinge region of only three amino acids. The two TR subtypes differ in the loop between helices 1 and 3, which could affect both ligand recognition and the effects of ligand in binding coactivators and corepressors. The two subtypes also differ in a single amino acid residue in the hormone-binding pocket, Asn (TR beta) for Ser (TR alpha). Studies here with TRs in which the subtype-specific residue is exchanged suggest that most of the selectivity in binding derives from this amino acid difference. The flexibility of the polar region in the TR beta receptor, combined with differential recognition of the chemical group at the 1-carbon position, seems to stabilize the complex with GC-1 and contribute to its beta -selectivity. These results suggest a strategy for development of subtype-specific compounds involving modifications of the ligand at the 1-position.
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