6b31

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==Structure of RORgt in complex with a novel inverse agonist 2==
==Structure of RORgt in complex with a novel inverse agonist 2==
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<StructureSection load='6b31' size='340' side='right' caption='[[6b31]], [[Resolution|resolution]] 3.18&Aring;' scene=''>
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<StructureSection load='6b31' size='340' side='right'caption='[[6b31]], [[Resolution|resolution]] 3.18&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6b31]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B31 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B31 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6b31]] 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=6B31 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6B31 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=CFJ:(3S)-N~1~-(3-chloro-4-cyanophenyl)-N~5~-(1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-3-methylpentanediamide'>CFJ</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=6b31 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b31 OCA], [http://pdbe.org/6b31 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b31 RCSB], [http://www.ebi.ac.uk/pdbsum/6b31 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b31 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=CFJ:(3S)-N~1~-(3-chloro-4-cyanophenyl)-N~5~-(1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-3-methylpentanediamide'>CFJ</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=6b31 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b31 OCA], [https://pdbe.org/6b31 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6b31 RCSB], [https://www.ebi.ac.uk/pdbsum/6b31 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6b31 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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Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORgammat) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORgammat inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORgammat protein was also observed.
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Identification of novel quinazolinedione derivatives as RORgammat inverse agonist.,Fukase Y, Sato A, Tomata Y, Ochida A, Kono M, Yonemori K, Koga K, Okui T, Yamasaki M, Fujitani Y, Nakagawa H, Koyama R, Nakayama M, Skene R, Sang BC, Hoffman I, Shirai J, Yamamoto S Bioorg Med Chem. 2018 Feb 1;26(3):721-736. doi: 10.1016/j.bmc.2017.12.039. Epub, 2017 Dec 28. PMID:29342416<ref>PMID:29342416</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 6b31" 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: Signaling protein]]
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[[Category: Signaling protein-agonist complex]]
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Current revision

Structure of RORgt in complex with a novel inverse agonist 2

PDB ID 6b31

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