View source for 7rio


==human PXR LBD bound to GSK003==
<StructureSection load='7rio' size='340' side='right'caption='[[7rio]], [[Resolution|resolution]] 2.48&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7rio]] 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=7RIO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RIO FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5YX:N-[3-(2-tert-butyl-5-{2-[2-(methanesulfonyl)ethyl]pyrimidin-4-yl}-1,3-thiazol-4-yl)-2-fluorophenyl]-2,5-difluorobenzene-1-sulfonamide'>5YX</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7n2a|7n2a]]</div></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR1I2, PXR ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=7rio FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rio OCA], [https://pdbe.org/7rio PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rio RCSB], [https://www.ebi.ac.uk/pdbsum/7rio PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rio ProSAT]</span></td></tr>
</table>
== Function ==
[[https://www.uniprot.org/uniprot/NR1I2_HUMAN NR1I2_HUMAN]] Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.<ref>PMID:9727070</ref> <ref>PMID:11668216</ref> <ref>PMID:11297522</ref> <ref>PMID:19297428</ref> <ref>PMID:12578355</ref> <ref>PMID:18768384</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The pregnane X receptor (PXR) regulates expression of proteins responsible for all three phases required for the detoxification mechanism, which include CYP450 enzymes, phase II enzymes, and multidrug efflux pumps. Therefore, PXR is a prominent receptor that is responsible for xenobiotic excretion and drug-drug interactions. Pyrimidinone 1 is an antagonist of the calcium sensing receptor (CaSR) and a strong activator of PXR. Repeat oral administration revealed diminished exposures over time, which prohibited further progression. A medicinal chemistry campaign was initiated to understand and abolish activation of PXR in order to increase systemic exposures. Rational structure-activity relationship investigations utilizing cocrystal structures and a de novo pharmacophore model resulted in compounds devoid of PXR activation. These studies culminated in the first orally active CaSR antagonist 8 suitable for progression. Cocrystallography, the pharmacophore model employed, and additional observations reported herein supported rational elimination of PXR activation and have applicability across diverse chemical classes to help erase PXR-driven drug-drug interactions.

Overcoming the Pregnane X Receptor Liability: Rational Design to Eliminate PXR-Mediated CYP Induction.,Ramanjulu JM, Williams SP, Lakdawala AS, DeMartino MP, Lan Y, Marquis RW ACS Med Chem Lett. 2021 Aug 10;12(9):1396-1404. doi:, 10.1021/acsmedchemlett.1c00187. eCollection 2021 Sep 9. PMID:34531948<ref>PMID:34531948</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7rio" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Ward, P]]
[[Category: Williams, S P]]
[[Category: Wisely, G B]]
[[Category: Gene regulation]]
[[Category: Helical sandwhich]]
[[Category: Nuclear receptor]]