Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor

被引:108
作者
Borngraeber, S
Budny, MJ
Chiellini, G
Cunha-Lima, ST
Togashi, M
Webb, P
Baxter, JD
Scanlan, TS
Fletterick, RJ
机构
[1] Univ Calif San Francisco, Dept Biochem & Biophys, Ctr Diabet, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Biochem Biophys, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Pharmaceut Chem & Mol & Cellular Pharmacol, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, Metab Res Unit, San Francisco, CA 94143 USA
关键词
D O I
10.1073/pnas.2136689100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Selective therapeutics for nuclear receptors would revolutionize treatment for endocrine disease. Specific control of nuclear receptor activity is challenging because the internal cavities that bind hormones can be virtually identical. Only one highly selective hormone analog is known for the thyroid receptor, GC-24, an agonist for human thyroid hormone receptor beta. The compound differs from natural hormone in benzyl, substituting for an iodine atom in the 3' position. The benzyl is too large to fit into the enclosed pocket of the receptor. The crystal structure of human thyroid hormone receptor beta at 2.8-Angstrom resolution with GC-24 bound explains its agonist activity and unique isoform specificity. The benzyl of GC-24 is accommodated through shifts of 3-4 Angstrom in two helices. These helices are required for binding hormone and positioning the critical helix 12 at the C terminus. Despite these changes, the complex associates with coactivator as tightly as human thyroid hormone receptor bound to thyroid hormone and is fully active. Our data suggest that increased specificity of ligand recognition derives from creating a new hydrophobic cluster with ligand and protein components.
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收藏
页码:15358 / 15363
页数:6
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