2pin

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[[Image:2pin.jpg|left|200px]]
[[Image:2pin.jpg|left|200px]]
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{{Structure
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<!--
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|PDB= 2pin |SIZE=350|CAPTION= <scene name='initialview01'>2pin</scene>, resolution 2.3&Aring;
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The line below this paragraph, containing "STRUCTURE_2pin", creates the "Structure Box" on the page.
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|SITE= <scene name='pdbsite=AC1:So4+Binding+Site+For+Residue+B+501'>AC1</scene>, <scene name='pdbsite=AC2:4hy+Binding+Site+For+Residue+A+500'>AC2</scene>, <scene name='pdbsite=AC3:4hy+Binding+Site+For+Residue+B+500'>AC3</scene>, <scene name='pdbsite=AC4:Leg+Binding+Site+For+Residue+A+501'>AC4</scene> and <scene name='pdbsite=AC5:Leg+Binding+Site+For+Residue+B+502'>AC5</scene>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=4HY:[4-(4-HYDROXY-3-IODO-PHENOXY)-3,5-DIIODO-PHENYL]-ACETIC+ACID'>4HY</scene>, <scene name='pdbligand=LEG:1-(4-HEXYLPHENYL)PROP-2-EN-1-ONE'>LEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY=
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or leave the SCENE parameter empty for the default display.
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|GENE= THRB, ERBA2, NR1A2, THR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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-->
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|DOMAIN=
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{{STRUCTURE_2pin| PDB=2pin | SCENE= }}
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|RELATEDENTRY=[[2pio|2PIO]], [[2pip|2PIP]], [[2piq|2PIQ]], [[2pir|2PIR]], [[2pit|2PIT]], [[2piu|2PIU]], [[2piv|2PIV]], [[2piw|2PIW]], [[2pix|2PIX]], [[2pkl|2PKL]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2pin FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pin OCA], [http://www.ebi.ac.uk/pdbsum/2pin PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2pin RCSB]</span>
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}}
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'''Thyroid receptor beta in complex with inhibitor'''
'''Thyroid receptor beta in complex with inhibitor'''
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[[Category: Jouravel, N.]]
[[Category: Jouravel, N.]]
[[Category: Webb, P.]]
[[Category: Webb, P.]]
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[[Category: af-2 pocket]]
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[[Category: Af-2 pocket]]
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[[Category: aromatic-beta-amino ketone]]
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[[Category: Aromatic-beta-amino ketone]]
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[[Category: coregulator binding]]
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[[Category: Coregulator binding]]
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[[Category: hormone receptor]]
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[[Category: Hormone receptor]]
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[[Category: inhibitor]]
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[[Category: Inhibitor]]
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[[Category: nuclear receptor]]
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[[Category: Nuclear receptor]]
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[[Category: protein-protein interaction]]
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[[Category: Protein-protein interaction]]
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[[Category: structure-based drug design]]
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[[Category: Structure-based drug design]]
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[[Category: surface interacting drug]]
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[[Category: Surface interacting drug]]
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[[Category: thyroid receptor beta]]
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[[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 Mar 31 04:36:24 2008''
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Revision as of 10:11, 4 May 2008

Image:2pin.jpg

Template:STRUCTURE 2pin

Thyroid receptor beta in complex with inhibitor


Overview

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.

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 Sun May 4 13:11:08 2008

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OCA

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