5c4u

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==Identification of a Novel Allosteric Binding Site for RORgt Inhibitors==
==Identification of a Novel Allosteric Binding Site for RORgt Inhibitors==
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<StructureSection load='5c4u' size='340' side='right' caption='[[5c4u]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
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<StructureSection load='5c4u' size='340' side='right'caption='[[5c4u]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5c4u]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5C4U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5C4U FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5c4u]] is a 1 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=5C4U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5C4U 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=4Y7:4-{1-[2-CHLORO-6-(TRIFLUOROMETHYL)BENZOYL]-1H-PYRAZOLO[4,3-B]PYRIDIN-3-YL}-5-FLUORO-2-HYDROXYBENZOIC+ACID'>4Y7</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 2.08&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5c4o|5c4o]], [[5c4s|5c4s]], [[5c4t|5c4t]]</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=4Y7:4-{1-[2-CHLORO-6-(TRIFLUOROMETHYL)BENZOYL]-1H-PYRAZOLO[4,3-B]PYRIDIN-3-YL}-5-FLUORO-2-HYDROXYBENZOIC+ACID'>4Y7</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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=5c4u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c4u OCA], [http://pdbe.org/5c4u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5c4u RCSB], [http://www.ebi.ac.uk/pdbsum/5c4u PDBsum]</span></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=5c4u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c4u OCA], [https://pdbe.org/5c4u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5c4u RCSB], [https://www.ebi.ac.uk/pdbsum/5c4u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5c4u ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/RORG_HUMAN RORG_HUMAN]] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.
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[https://www.uniprot.org/uniprot/RORG_HUMAN RORG_HUMAN] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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RORgammat is critical for the differentiation and proliferation of Th17 cells associated with several chronic autoimmune diseases. We report the discovery of a novel allosteric binding site on the nuclear receptor RORgammat. Co-crystallization of the ligand binding domain (LBD) of RORgammat with a series of small-molecule antagonists demonstrates occupancy of a previously unreported allosteric binding pocket. Binding at this non-canonical site induces an unprecedented conformational reorientation of helix 12 in the RORgammat LBD, which blocks cofactor binding. The functional consequence of this allosteric ligand-mediated conformation is inhibition of function as evidenced by both biochemical and cellular studies. RORgammat function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric RORgammat ligands. This brings forward an approach to target RORgammat for the treatment of Th17-mediated autoimmune diseases. The elucidation of an unprecedented modality of pharmacological antagonism establishes a mechanism for modulation of nuclear receptors.
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Identification of an allosteric binding site for RORgammat inhibition.,Scheepstra M, Leysen S, van Almen GC, Miller JR, Piesvaux J, Kutilek V, van Eenennaam H, Zhang H, Barr K, Nagpal S, Soisson SM, Kornienko M, Wiley K, Elsen N, Sharma S, Correll CC, Trotter BW, van der Stelt M, Oubrie A, Ottmann C, Parthasarathy G, Brunsveld L Nat Commun. 2015 Dec 7;6:8833. doi: 10.1038/ncomms9833. PMID:26640126<ref>PMID:26640126</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 5c4u" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Parthasarathy, G]]
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[[Category: Homo sapiens]]
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[[Category: Soisson, S]]
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[[Category: Large Structures]]
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[[Category: Allosteric]]
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[[Category: Parthasarathy G]]
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[[Category: Inhibitor]]
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[[Category: Soisson S]]
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[[Category: Transcription-transcription inhibitor complex]]
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Current revision

Identification of a Novel Allosteric Binding Site for RORgt Inhibitors

PDB ID 5c4u

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