6bn6

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==IDENTIFICATION OF BICYCLIC HEXAFLUOROISOPROPYL ALCOHOL SULFONAMIDES AS RORGT/RORC INVERSE AGONISTS==
==IDENTIFICATION OF BICYCLIC HEXAFLUOROISOPROPYL ALCOHOL SULFONAMIDES AS RORGT/RORC INVERSE AGONISTS==
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<StructureSection load='6bn6' size='340' side='right' caption='[[6bn6]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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<StructureSection load='6bn6' size='340' side='right'caption='[[6bn6]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6bn6]] is a 2 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=6BN6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BN6 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6bn6]] 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=6BN6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BN6 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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=XGH:2-[(2S)-4-[(4-fluorophenyl)sulfonyl]-7-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]-N-(2-hydroxy-2-methylpropyl)acetamide'>XGH</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='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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=XGH:2-[(2S)-4-[(4-fluorophenyl)sulfonyl]-7-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]-N-(2-hydroxy-2-methylpropyl)acetamide'>XGH</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=6bn6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bn6 OCA], [http://pdbe.org/6bn6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bn6 RCSB], [http://www.ebi.ac.uk/pdbsum/6bn6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bn6 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=6bn6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bn6 OCA], [https://pdbe.org/6bn6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bn6 RCSB], [https://www.ebi.ac.uk/pdbsum/6bn6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bn6 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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We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORgammat inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor alpha (LXRalpha). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRalpha activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.
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Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORgamma/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity.,Gong H, Weinstein DS, Lu Z, Duan JJ, Stachura S, Haque L, Karmakar A, Hemagiri H, Raut DK, Gupta AK, Khan J, Camac D, Sack JS, Pudzianowski A, Wu DR, Yarde M, Shen DR, Borowski V, Xie JH, Sun H, D'Arienzo C, Dabros M, Galella MA, Wang F, Weigelt CA, Zhao Q, Foster W, Somerville JE, Salter-Cid LM, Barrish JC, Carter PH, Dhar TGM Bioorg Med Chem Lett. 2018 Jan 15;28(2):85-93. doi: 10.1016/j.bmcl.2017.12.006., Epub 2017 Dec 5. PMID:29233651<ref>PMID:29233651</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 6bn6" 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: Sack, J]]
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[[Category: Large Structures]]
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[[Category: Inverse agonist]]
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[[Category: Sack J]]
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[[Category: Ligand-binding domain]]
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[[Category: Nuclear hormone receptor]]
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[[Category: Rorgt]]
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[[Category: Transcription-transcription inhibitor complex]]
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Current revision

IDENTIFICATION OF BICYCLIC HEXAFLUOROISOPROPYL ALCOHOL SULFONAMIDES AS RORGT/RORC INVERSE AGONISTS

PDB ID 6bn6

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