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2pin

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{{STRUCTURE_2pin| PDB=2pin | SCENE= }}
{{STRUCTURE_2pin| PDB=2pin | SCENE= }}
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'''Thyroid receptor beta in complex with inhibitor'''
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===Thyroid receptor beta in complex with inhibitor===
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==Overview==
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The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic beta-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor beta (TRbeta), in a high-throughput screen. Initial evidence suggested that the aromatic beta-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRbeta surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TRbeta with the inhibitor HPPE at 2.3-A resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRbeta and its coactivator. Several lines of evidence, including experiments with TRbeta mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRbeta, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) beta-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRbeta. DHPPA represents a novel class of potent TRbeta antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription.
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==About this Structure==
==About this Structure==
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[[Category: Surface interacting drug]]
[[Category: Surface interacting drug]]
[[Category: Thyroid receptor beta]]
[[Category: Thyroid receptor beta]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 13:11:08 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 06:19:42 2008''

Revision as of 03:19, 28 July 2008

Image:2pin.png

Template:STRUCTURE 2pin

Thyroid receptor beta in complex with inhibitor

Template:ABSTRACT PUBMED 17823305

About this Structure

2PIN is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structural insight into the mode of action of a direct inhibitor of coregulator binding to the thyroid hormone receptor., Estebanez-Perpina E, Arnold LA, Jouravel N, Togashi M, Blethrow J, Mar E, Nguyen P, Phillips KJ, Baxter JD, Webb P, Guy RK, Fletterick RJ, Mol Endocrinol. 2007 Dec;21(12):2919-28. Epub 2007 Sep 6. PMID:17823305

Page seeded by OCA on Mon Jul 28 06:19:42 2008

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