2pin

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[[Image:2pin.jpg|left|200px]]
 
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{{Structure
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==Thyroid receptor beta in complex with inhibitor==
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|PDB= 2pin |SIZE=350|CAPTION= <scene name='initialview01'>2pin</scene>, resolution 2.3&Aring;
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<StructureSection load='2pin' size='340' side='right'caption='[[2pin]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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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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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=4HY:[4-(4-HYDROXY-3-IODO-PHENOXY)-3,5-DIIODO-PHENYL]-ACETIC+ACID'>4HY</scene> and <scene name='pdbligand=LEG:'>LEG</scene>
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<table><tr><td colspan='2'>[[2pin]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PIN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2PIN FirstGlance]. <br>
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|ACTIVITY=
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
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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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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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></td></tr>
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}}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2pin FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pin OCA], [https://pdbe.org/2pin PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2pin RCSB], [https://www.ebi.ac.uk/pdbsum/2pin PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2pin ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/THB_HUMAN THB_HUMAN] Defects in THRB are the cause of generalized thyroid hormone resistance (GTHR) [MIM:[https://omim.org/entry/188570 188570]. GTHR is a disease characterized by goiter, abnormal mental functions, increased susceptibility to infections, abnormal growth and bone maturation, tachycardia and deafness. Affected individuals may also have attention deficit-hyperactivity disorders (ADHD) and language difficulties. GTHR patients also have high levels of circulating thyroid hormones (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH).<ref>PMID:2510172</ref> <ref>PMID:2153155</ref> <ref>PMID:1846005</ref> <ref>PMID:1661299</ref> <ref>PMID:1653889</ref> <ref>PMID:1563081</ref> <ref>PMID:1314846</ref> <ref>PMID:1619012</ref> <ref>PMID:1587388</ref> <ref>PMID:1324420</ref> <ref>PMID:8514853</ref> <ref>PMID:8175986</ref> <ref>PMID:7833659</ref> <ref>PMID:8664910</ref> <ref>PMID:8889584</ref> <ref>PMID:10660344</ref> <ref>PMID:16804041</ref> <ref>PMID:19268523</ref> Defects in THRB are the cause of generalized thyroid hormone resistance autosomal recessive (GTHRAR) [MIM:[https://omim.org/entry/274300 274300]. An autosomal recessive disorder characterized by goiter, clinical euthyroidism, end-organ unresponsiveness to thyroid hormone, abnormal growth and bone maturation, and deafness. Patients also have high levels of circulating thyroid hormones, with elevated thyroid stimulating hormone. Defects in THRB are the cause of selective pituitary thyroid hormone resistance (PRTH) [MIM:[https://omim.org/entry/145650 145650]; also known as familial hyperthyroidism due to inappropriate thyrotropin secretion. PRTH is a variant form of thyroid hormone resistance and is characterized by clinical hyperthyroidism, with elevated free thyroid hormones, but inappropriately normal serum TSH. Unlike GRTH, where the syndrome usually segregates with a dominant allele, the mode of inheritance in PRTH has not been established.<ref>PMID:7528740</ref> <ref>PMID:8381821</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/THB_HUMAN THB_HUMAN] High affinity receptor for triiodothyronine.<ref>PMID:17418816</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pi/2pin_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2pin ConSurf].
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<div style="clear:both"></div>
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'''Thyroid receptor beta in complex with inhibitor'''
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==See Also==
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*[[Thyroid hormone receptor 3D structures|Thyroid hormone receptor 3D structures]]
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== References ==
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==Overview==
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<references/>
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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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__TOC__
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</StructureSection>
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==About this Structure==
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2PIN is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PIN OCA].
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==Reference==
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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:[http://www.ncbi.nlm.nih.gov/pubmed/17823305 17823305]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Baxter, J D.]]
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[[Category: Baxter JD]]
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[[Category: Estebanez-Perpina, E.]]
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[[Category: Estebanez-Perpina E]]
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[[Category: Fletterick, R J.]]
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[[Category: Fletterick RJ]]
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[[Category: Guy, L R.]]
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[[Category: Guy LR]]
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[[Category: Jouravel, N.]]
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[[Category: Jouravel N]]
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[[Category: Webb, P.]]
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[[Category: Webb P]]
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[[Category: 4HY]]
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[[Category: LEG]]
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[[Category: SO4]]
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[[Category: af-2 pocket]]
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[[Category: aromatic-beta-amino ketone]]
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[[Category: coregulator binding]]
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[[Category: hormone receptor]]
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[[Category: inhibitor]]
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[[Category: nuclear receptor]]
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[[Category: protein-protein interaction]]
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[[Category: structure-based drug design]]
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[[Category: surface interacting drug]]
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[[Category: thyroid receptor beta]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:13:26 2008''
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Current revision

Thyroid receptor beta in complex with inhibitor

PDB ID 2pin

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