View source for 7kxe


==CRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C (NHIS-RORGT(244-487)-L6-SRC1(678-692)) IN COMPLEX WITH {3,5-DICHLORO-4-[4-METHOXY-3-(PROPAN-2-YL)PHENOXY]PHENYL}METHANOL==
<StructureSection load='7kxe' size='340' side='right'caption='[[7kxe]], [[Resolution|resolution]] 2.42&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7kxe]] 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=7KXE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KXE FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.42&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Z7H:N-{3,5-dichloro-4-[4-methoxy-3-(propan-2-yl)phenoxy]phenyl}-2-(pyridin-3-yl)acetamide'>Z7H</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=7kxe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kxe OCA], [https://pdbe.org/7kxe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kxe RCSB], [https://www.ebi.ac.uk/pdbsum/7kxe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kxe ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN] Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children.
== 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.[https://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN] Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.<ref>PMID:9427757</ref> <ref>PMID:7481822</ref> <ref>PMID:9223431</ref> <ref>PMID:9296499</ref> <ref>PMID:9223281</ref> <ref>PMID:10449719</ref> <ref>PMID:12954634</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor gammat (RORgammat) agonists is described. Compound 1 was identified from deck mining as a RORgammat agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. (c)2020 Elsevier Science Ltd. All rights reserved.

Substituted diaryl ether compounds as retinoic acid-related orphan Receptor-gammat (RORgammat) agonists.,Ruan Z, Park PK, Wei D, Purandare A, Wan H, O'Malley D, Stachura S, Perez H, Cavallaro CL, Weigelt CA, Sack JS, Ruzanov M, Khan J, Gururajan M, Wong JJ, Huang Y, Yarde M, Li Z, Chen C, Sun H, Borowski V, Xie JH, Anthony M, Agler M, Fink BE, Harikrishnan LS Bioorg Med Chem Lett. 2021 Mar 1;35:127778. doi: 10.1016/j.bmcl.2021.127778. Epub , 2021 Jan 8. PMID:33422603<ref>PMID:33422603</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7kxe" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Sack J]]