7kqj
From Proteopedia
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==CRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C (NHIS-RORGT(244-487)-L6-SRC1(678-692) IN COMPLEX WITH A NOVEL TRICYCLIC-CARBOCYLIC RORGT INVERSE AGONIST== | ==CRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C (NHIS-RORGT(244-487)-L6-SRC1(678-692) IN COMPLEX WITH A NOVEL TRICYCLIC-CARBOCYLIC RORGT INVERSE AGONIST== | ||
| - | <StructureSection load='7kqj' size='340' side='right'caption='[[7kqj]]' scene=''> | + | <StructureSection load='7kqj' size='340' side='right'caption='[[7kqj]], [[Resolution|resolution]] 2.65Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KQJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KQJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7kqj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KQJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KQJ FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7kqj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kqj OCA], [https://pdbe.org/7kqj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kqj RCSB], [https://www.ebi.ac.uk/pdbsum/7kqj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kqj ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Z8G:N-[(3R,3aS,9bS)-9b-[(4-fluorophenyl)sulfonyl]-7-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl]-2-hydroxy-2-methylpropanamide'>Z8G</scene></td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7kqj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kqj OCA], [https://pdbe.org/7kqj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kqj RCSB], [https://www.ebi.ac.uk/pdbsum/7kqj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kqj ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [[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. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | SAR efforts directed at identifying RORgammat inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3-7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORgammat revealed several key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasis-the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1. | ||
| + | |||
| + | Tricyclic-Carbocyclic RORgammat Inverse Agonists-Discovery of BMS-986313.,Yang MG, Beaudoin-Bertrand M, Xiao Z, Marcoux D, Weigelt CA, Yip S, Wu DR, Ruzanov M, Sack JS, Wang J, Yarde M, Li S, Shuster DJ, Xie JH, Sherry T, Obermeier MT, Fura A, Stefanski K, Cornelius G, Khandelwal P, Karmakar A, Basha M, Babu V, Gupta AK, Mathur A, Salter-Cid L, Denton R, Zhao Q, Dhar TGM J Med Chem. 2021 Feb 16. doi: 10.1021/acs.jmedchem.0c01992. PMID:33591748<ref>PMID:33591748</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7kqj" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Sack | + | [[Category: Sack, J S]] |
| + | [[Category: Ligand-binding domain]] | ||
| + | [[Category: Nuclear hormone receptor]] | ||
| + | [[Category: Rorgt]] | ||
| + | [[Category: Transcription]] | ||
| + | [[Category: Transcription-agonist complex]] | ||
Revision as of 06:54, 24 March 2021
CRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C (NHIS-RORGT(244-487)-L6-SRC1(678-692) IN COMPLEX WITH A NOVEL TRICYCLIC-CARBOCYLIC RORGT INVERSE AGONIST
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