6cvh

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==Identification and biological evaluation of thiazole-based inverse agonists of RORgt==
==Identification and biological evaluation of thiazole-based inverse agonists of RORgt==
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<StructureSection load='6cvh' size='340' side='right' caption='[[6cvh]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
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<StructureSection load='6cvh' size='340' side='right'caption='[[6cvh]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6cvh]] 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=6CVH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CVH FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6cvh]] 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=6CVH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CVH 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=FJG:trans-3-({4-(cyclohexylmethyl)-5-[3-(1-methylcyclopropyl)-5-{[(2R)-1,1,1-trifluoropropan-2-yl]carbamoyl}phenyl]-1,3-thiazole-2-carbonyl}amino)cyclobutane-1-carboxylic+acid'>FJG</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]] 3.5&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RORC, NR1F3, RORG, RZRG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=FJG:trans-3-({4-(cyclohexylmethyl)-5-[3-(1-methylcyclopropyl)-5-{[(2R)-1,1,1-trifluoropropan-2-yl]carbamoyl}phenyl]-1,3-thiazole-2-carbonyl}amino)cyclobutane-1-carboxylic+acid'>FJG</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=6cvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cvh OCA], [http://pdbe.org/6cvh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cvh RCSB], [http://www.ebi.ac.uk/pdbsum/6cvh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cvh ProSAT]</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=6cvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cvh OCA], [https://pdbe.org/6cvh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cvh RCSB], [https://www.ebi.ac.uk/pdbsum/6cvh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cvh 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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The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORgammat) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORgammat lies at the core of this pathway and represents an attractive opportunity for intervention with a small molecule. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORgammat drug discovery. We describe the discovery and evaluation of a new class of potent and selective RORgammat inverse agonists based on a thiazole core. Acid analog 1j demonstrated oral bioavailability in rats and was potent in a human whole blood assay, suggesting potential utility in treating autoimmune and inflammatory diseases such as psoriasis. X-ray crystallographic data helped to elucidate the molecular mechanism for RORgammat inhibition with this series.
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Identification and biological evaluation of thiazole-based inverse agonists of RORgammat.,Gege C, Cummings MD, Albers M, Kinzel O, Kleymann G, Schluter T, Steeneck C, Nelen MI, Milligan C, Spurlino J, Xue X, Leonard K, Edwards JP, Fourie A, Goldberg SD, Hoffmann T Bioorg Med Chem Lett. 2018 May 15;28(9):1446-1455. doi:, 10.1016/j.bmcl.2018.03.093. Epub 2018 Apr 3. PMID:29631962<ref>PMID:29631962</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 6cvh" 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]]
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[[Category: Milligan, C]]
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[[Category: Large Structures]]
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[[Category: Spurlino, J]]
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[[Category: Milligan C]]
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[[Category: Nuclear protein]]
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[[Category: Spurlino J]]
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[[Category: Nuclear receptor rorgt]]
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Current revision

Identification and biological evaluation of thiazole-based inverse agonists of RORgt

PDB ID 6cvh

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