1q4x

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Revision as of 16:44, 12 November 2007

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spinqualitylabelsall models 1q4x, resolution 2.8Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal Structure of Human Thyroid Hormone Receptor beta LBD in complex with specific agonist GC-24

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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-A 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 A 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.

Disease

Known diseases associated with this structure: Thyroid hormone resistance OMIM:[190160], Thyroid hormone resistance, autosomal recessive OMIM:[190160]

About this Structure

1Q4X is a Single protein structure of sequence from Homo sapiens with G24 as ligand. Full crystallographic information is available from OCA.

Reference

Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor., Borngraeber S, Budny MJ, Chiellini G, Cunha-Lima ST, Togashi M, Webb P, Baxter JD, Scanlan TS, Fletterick RJ, Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15358-63. Epub 2003 Dec 12. PMID:14673100

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