4oc7

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==Retinoic acid receptor alpha in complex with (E)-3-(3'-allyl-6-hydroxy-[1,1'-biphenyl]-3-yl)acrylic acid and a fragment of the coactivator TIF2==
==Retinoic acid receptor alpha in complex with (E)-3-(3'-allyl-6-hydroxy-[1,1'-biphenyl]-3-yl)acrylic acid and a fragment of the coactivator TIF2==
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<StructureSection load='4oc7' size='340' side='right' caption='[[4oc7]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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<StructureSection load='4oc7' size='340' side='right'caption='[[4oc7]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4oc7]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OC7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OC7 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4oc7]] 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=4OC7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OC7 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2QO:(2E)-3-[6-HYDROXY-3-(PROP-2-EN-1-YL)BIPHENYL-3-YL]PROP-2-ENOIC+ACID'>2QO</scene></td></tr>
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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]] 2.5&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4oc7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4oc7 OCA], [http://pdbe.org/4oc7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4oc7 RCSB], [http://www.ebi.ac.uk/pdbsum/4oc7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4oc7 ProSAT]</span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2QO:(2E)-3-[6-HYDROXY-3-(PROP-2-EN-1-YL)BIPHENYL-3-YL]PROP-2-ENOIC+ACID'>2QO</scene></td></tr>
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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=4oc7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4oc7 OCA], [https://pdbe.org/4oc7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4oc7 RCSB], [https://www.ebi.ac.uk/pdbsum/4oc7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4oc7 ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
 
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[[http://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN]] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation.
 
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/RXRA_HUMAN RXRA_HUMAN]] Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.<ref>PMID:10195690</ref> <ref>PMID:11162439</ref> <ref>PMID:11915042</ref> <ref>PMID:20215566</ref> [[http://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN]] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.<ref>PMID:9430642</ref>
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[https://www.uniprot.org/uniprot/RXRA_HUMAN RXRA_HUMAN] Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.<ref>PMID:10195690</ref> <ref>PMID:11162439</ref> <ref>PMID:11915042</ref> <ref>PMID:20215566</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Small ligands are a powerful way to control the function of protein complexes via dynamic binding interfaces. The classic example is found in gene transcription where small ligands regulate nuclear receptor binding to coactivator proteins via the dynamic activation function 2 (AF2) interface. Current ligands target the ligand-binding pocket side of the AF2. Few ligands are known, which selectively target the coactivator side of the AF2, or which can be selectively switched from one side of the interface to the other. We use NMR spectroscopy and modeling to identify a natural product, which targets the retinoid X receptor (RXR) at both sides of the AF2. We then use chemical synthesis, cellular screening and X-ray co-crystallography to split this dual activity, leading to a potent and molecularly efficient RXR agonist, and a first-of-kind inhibitor selective for the RXR/coactivator interaction. Our findings justify future exploration of natural products at dynamic protein interfaces.
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A natural-product switch for a dynamic protein interface.,Scheepstra M, Nieto L, Hirsch AK, Fuchs S, Leysen S, Lam CV, in het Panhuis L, van Boeckel CA, Wienk H, Boelens R, Ottmann C, Milroy LG, Brunsveld L Angew Chem Int Ed Engl. 2014 Jun 16;53(25):6443-8. doi: 10.1002/anie.201403773., Epub 2014 May 12. PMID:24821627<ref>PMID:24821627</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4oc7" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Retinoid X receptor|Retinoid X receptor]]
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*[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Brunsveld, L]]
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[[Category: Homo sapiens]]
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[[Category: Leysen, S]]
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[[Category: Large Structures]]
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[[Category: Milroy, L G]]
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[[Category: Brunsveld L]]
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[[Category: Ottmann, C]]
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[[Category: Leysen S]]
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[[Category: Scheepstra, M]]
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[[Category: Milroy LG]]
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[[Category: Ligand binding domain]]
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[[Category: Ottmann C]]
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[[Category: Transcription]]
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[[Category: Scheepstra M]]

Current revision

Retinoic acid receptor alpha in complex with (E)-3-(3'-allyl-6-hydroxy-[1,1'-biphenyl]-3-yl)acrylic acid and a fragment of the coactivator TIF2

PDB ID 4oc7

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