Hormone selectivity in thyroid hormone receptors

Citation
Rl. Wagner et al., Hormone selectivity in thyroid hormone receptors, MOL ENDOCR, 15(3), 2001, pp. 398-410
Citations number
49
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Endocrinology, Nutrition & Metabolism
Journal title
MOLECULAR ENDOCRINOLOGY
ISSN journal
0888-8809 → ACNP
Volume
15
Issue
3
Year of publication
2001
Pages
398 - 410
Database
ISI
SICI code
0888-8809(200103)15:3<398:HSITHR>2.0.ZU;2-8
Abstract
Separate genes encode thyroid hormone receptor subtypes TR alpha (NR1A1) an d 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 hypercholesterol emia. We previously determined the crystal structure of the rat (r) TR alph a ligand-binding domain (LBD). In the present study, we determined the crys tal 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)-ph enoxy acetic acid]. The rTR alpha and hTR beta LBDs show close structural s imilarity. However, the hTR beta structures extend into the DNA-binding dom ain 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, whi ch could affect both ligand recognition and the effects of ligand in bindin g coactivators and corepressors. The two subtypes also differ in a single a mino 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 exch anged suggest that most of the selectivity in binding derives from this ami no acid difference. The flexibility of the polar region in the TR beta rece ptor, combined with differential recognition of the chemical group at the 1 -carbon position, seems to stabilize the complex with GC-1 and contribute t o its beta -selectivity. These results suggest a strategy for development o f subtype-specific compounds involving modifications of the ligand at the 1 -position.