6br2

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==Structure of RORgt in complex with a novel isoquinoline inverse agonist.==
==Structure of RORgt in complex with a novel isoquinoline inverse agonist.==
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<StructureSection load='6br2' size='340' side='right' caption='[[6br2]], [[Resolution|resolution]] 3.18&Aring;' scene=''>
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<StructureSection load='6br2' size='340' side='right'caption='[[6br2]], [[Resolution|resolution]] 3.18&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6br2]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BR2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BR2 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6br2]] 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=6BR2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BR2 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=E3S:(1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-[(3-oxo-2,3-dihydro-1,2-oxazol-5-yl)acetyl]-1,2,3,4-tetrahydroisoquinoline-1-carboxamide'>E3S</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</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]] 3.18&#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=6br2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6br2 OCA], [http://pdbe.org/6br2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6br2 RCSB], [http://www.ebi.ac.uk/pdbsum/6br2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6br2 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=E3S:(1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-[(3-oxo-2,3-dihydro-1,2-oxazol-5-yl)acetyl]-1,2,3,4-tetrahydroisoquinoline-1-carboxamide'>E3S</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</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=6br2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6br2 OCA], [https://pdbe.org/6br2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6br2 RCSB], [https://www.ebi.ac.uk/pdbsum/6br2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6br2 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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A series of tetrahydronaphthyridine derivatives as novel RORgammat inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower log D value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [ cis-3-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORgammat inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound 10 exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound 10 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.
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Discovery of [ cis-3-({(5 R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor gammat Inverse Agonist.,Kono M, Ochida A, Oda T, Imada T, Banno Y, Taya N, Masada S, Kawamoto T, Yonemori K, Nara Y, Fukase Y, Yukawa T, Tokuhara H, Skene R, Sang BC, Hoffman ID, Snell GP, Uga K, Shibata A, Igaki K, Nakamura Y, Nakagawa H, Tsuchimori N, Yamasaki M, Shirai J, Yamamoto S J Med Chem. 2018 Mar 14. doi: 10.1021/acs.jmedchem.8b00061. PMID:29510038<ref>PMID:29510038</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 6br2" 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: Hoffman, I]]
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[[Category: Homo sapiens]]
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[[Category: Skene, R J]]
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[[Category: Large Structures]]
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[[Category: Complex]]
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[[Category: Hoffman I]]
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[[Category: Inverse agonist]]
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[[Category: Skene RJ]]
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[[Category: Nuclear hormone receptor]]
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[[Category: Transcription-agonist complex]]
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Current revision

Structure of RORgt in complex with a novel isoquinoline inverse agonist.

PDB ID 6br2

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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