1xzx

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Thyroxine-Thyroid Hormone Receptor Interactions

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Thyroid hormone (TH) actions are mediated by nuclear receptors (TRs alpha, and beta) that bind triiodothyronine (T(3), 3,5,3'-triiodo-l-thyronine), with high affinity, and its precursor thyroxine (T(4), 3,5,3',5'-tetraiodo-l-thyronine) with lower affinity. T(4) contains a, bulky 5' iodine group absent from T(3). Because T(3) is buried in the core, of the ligand binding domain (LBD), we have predicted that TH analogues, with 5' substituents should fit poorly into the ligand binding pocket and, perhaps behave as antagonists. We therefore examined how T(4) affects TR, activity and conformation. We obtained several lines of evidence (ligand, dissociation kinetics, migration on hydrophobic interaction columns, and, non-denaturing gels) that TR-T(4) complexes adopt a conformation that, differs from TR-T(3) complexes in solution. Nonetheless, T(4) behaves as, an agonist in vitro (in effects on coregulator and DNA binding) and in, cells, when conversion to T(3) does not contribute to agonist activity. We, determined x-ray crystal structures of the TRbeta LBD in complex with T(3), and T(4) at 2.5-A and 3.1-A resolution. Comparison of the structures, reveals that TRbeta accommodates T(4) through subtle alterations in the, loop connecting helices 11 and 12 and amino acid side chains in the, pocket, which, together, enlarge a niche that permits helix 12 to pack, over the 5' iodine and complete the coactivator binding surface. While, T(3) is the major active TH, our results suggest that T(4) could activate, nuclear TRs at appropriate concentrations. The ability of TR to adapt to, the 5' extension should be considered in TR ligand design.

Disease

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

About this Structure

1XZX is a Single protein structure of sequence from Homo sapiens with CAC and T3 as ligands. Full crystallographic information is available from OCA.

Reference

Thyroxine-thyroid hormone receptor interactions., Sandler B, Webb P, Apriletti JW, Huber BR, Togashi M, Cunha Lima ST, Juric S, Nilsson S, Wagner R, Fletterick RJ, Baxter JD, J Biol Chem. 2004 Dec 31;279(53):55801-8. Epub 2004 Oct 4. PMID:15466465

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