6o3z

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Current revision (14:50, 13 March 2024) (edit) (undo)
 
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<StructureSection load='6o3z' size='340' side='right'caption='[[6o3z]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
<StructureSection load='6o3z' size='340' side='right'caption='[[6o3z]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6o3z]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O3Z OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6O3Z FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6o3z]] 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=6O3Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O3Z FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LKY:3-cyano-N-(3-{[(3S)-4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl]methyl}-5-fluoro-2-methylphenyl)benzamide'>LKY</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]] 2.4&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6o3z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o3z OCA], [http://pdbe.org/6o3z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o3z RCSB], [http://www.ebi.ac.uk/pdbsum/6o3z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o3z 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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LKY:3-cyano-N-(3-{[(3S)-4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl]methyl}-5-fluoro-2-methylphenyl)benzamide'>LKY</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=6o3z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o3z OCA], [https://pdbe.org/6o3z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o3z RCSB], [https://www.ebi.ac.uk/pdbsum/6o3z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o3z ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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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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The retinoic acid receptor-related orphan nuclear receptor gammat (RORgammat), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORgammat with 1a, an analogue of the known piperazine RORgammat inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent RORgammat inverse agonist. Structure-activity relationship studies on 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, namely, 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)b utanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORgammat inhibitory activity and a favorable pharmacokinetic profile. Moreover, the in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production.
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Discovery of [1,2,4]Triazolo[1,5-a]pyridine Derivatives as Potent and Orally Bioavailable RORgammat Inverse Agonists.,Nakajima R, Oono H, Sugiyama S, Matsueda Y, Ida T, Kakuda S, Hirata J, Baba A, Makino A, Matsuyama R, White RD, Wurz RRho, Shin Y, Min X, Guzman-Perez A, Wang Z, Symons A, Singh SK, Mothe SR, Belyakov S, Chakrabarti A, Shuto S ACS Med Chem Lett. 2020 Feb 27;11(4):528-534. doi:, 10.1021/acsmedchemlett.9b00649. eCollection 2020 Apr 9. PMID:32292560<ref>PMID:32292560</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 6o3z" 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: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Min, X]]
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[[Category: Min X]]
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[[Category: Wang, Z]]
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[[Category: Wang Z]]
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[[Category: Protein binding]]
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[[Category: Retinoic acid receptor-related orphan receptor gt]]
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[[Category: Rorgt]]
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Current revision

Crystal structure of RORgt with 3-cyano-N-(3-{[(3S)-4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl]methyl}-5-fluoro-2-methylphenyl)benzamide (compound 1)

PDB ID 6o3z

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