1xzx

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{{STRUCTURE_1xzx| PDB=1xzx | SCENE= }}
{{STRUCTURE_1xzx| PDB=1xzx | SCENE= }}
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'''Thyroxine-Thyroid Hormone Receptor Interactions'''
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===Thyroxine-Thyroid Hormone Receptor Interactions===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_15466465}}
==About this Structure==
==About this Structure==
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[[Category: Webb, P.]]
[[Category: Webb, P.]]
[[Category: Hormone/growth factor receptor]]
[[Category: Hormone/growth factor receptor]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 15:42:47 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 03:57:02 2008''

Revision as of 00:57, 29 July 2008

Image:1xzx.png

Template:STRUCTURE 1xzx

Thyroxine-Thyroid Hormone Receptor Interactions

Template:ABSTRACT PUBMED 15466465

About this Structure

1XZX is a Single protein structure of sequence from Homo sapiens. 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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