7rio - Revision history

OCA at 16:31, 18 October 2023

OCA — Wed, 18 Oct 2023 16:31:57 GMT

←Older revision		Revision as of 16:31, 18 October 2023
Line 3:		Line 3:
	<StructureSection load='7rio' size='340' side='right'caption='[[7rio]], [[Resolution\|resolution]] 2.48Å' scene=''>		<StructureSection load='7rio' size='340' side='right'caption='[[7rio]], [[Resolution\|resolution]] 2.48Å' scene=''>
	== Structural highlights ==		== 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>	+	<table><tr><td colspan='2'>[[7rio]] 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=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>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.48Å</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='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='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>		<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>		</table>
	== Function ==		== 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>	+	[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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 20:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 7rio" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 7rio" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Pregnane X receptor 3D structures\|Pregnane X receptor 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Ward, P]]	+	[[Category: Ward P]]
-	[[Category: Williams~~, S P~~]]	+	[[Category: Williams SP]]
-	[[Category: Wisely~~, G B]]~~	+	[[Category: Wisely GB]]
-	~~[[Category: Gene regulation]]~~	+
-	~~[[Category: Helical sandwhich]]~~	+
-	~~[[Category: Nuclear receptor~~]]	+

OCA at 09:06, 29 September 2021

OCA — Wed, 29 Sep 2021 09:06:41 GMT

←Older revision		Revision as of 09:06, 29 September 2021
Line 1:		Line 1:

	==human PXR LBD bound to GSK003==		==human PXR LBD bound to GSK003==
-	<StructureSection load='7rio' size='340' side='right'caption='[[7rio]]' scene=''>	+	<StructureSection load='7rio' size='340' side='right'caption='[[7rio]], [[Resolution\|resolution]] 2.48Å' 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=7RIO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RIO FirstGlance]. <br>	+	<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='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>	+	</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>		</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®/PubMed®, 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__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Ward P]]	+	[[Category: Ward, P]]
-	[[Category: Williams SP]]	+	[[Category: Williams, S P]]
-	[[Category: Wisely GB]]	+	[[Category: Wisely, G B]]
		+	[[Category: Gene regulation]]
		+	[[Category: Helical sandwhich]]
		+	[[Category: Nuclear receptor]]

OCA at 06:21, 25 August 2021

OCA — Wed, 25 Aug 2021 06:21:11 GMT

←Older revision		Revision as of 06:21, 25 August 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7rio ~~is ON HOLD~~	+	==human PXR LBD bound to GSK003==
-		+	<StructureSection load='7rio' size='340' side='right'caption='[[7rio]]' scene=''>
-	~~Authors~~: ~~Williams~~, S.P., ~~Wisely~~, G.B., ~~Ward~~, P.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>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>
-	~~Description: human PXR LBD bound to GSK003~~	+	</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>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Williams, S.~~P]]	+	__TOC__
-	[[Category: ~~Wisely, G.B~~]]	+	</StructureSection>
-	[[Category: ~~Ward, P~~]]	+	[[Category: Large Structures]]
		+	[[Category: Ward P]]
		+	[[Category: Williams SP]]
		+	[[Category: Wisely GB]]

OCA: Protected "7rio" [edit=sysop:move=sysop]

OCA — Wed, 28 Jul 2021 09:37:27 GMT

Protected "7rio" [edit=sysop:move=sysop]

←Older revision

Revision as of 09:37, 28 July 2021

OCA: New page: '''Unreleased structure''' The entry 7rio is ON HOLD Authors: Williams, S.P., Wisely, G.B., Ward, P. Description: human PXR LBD bound to GSK003 Category: Unreleased Structures [[Ca...

OCA — Wed, 28 Jul 2021 09:37:26 GMT

New page: '''Unreleased structure''' The entry 7rio is ON HOLD Authors: Williams, S.P., Wisely, G.B., Ward, P. Description: human PXR LBD bound to GSK003 Category: Unreleased Structures [[Ca...

New page

'''Unreleased structure'''

The entry 7rio is ON HOLD

Authors: Williams, S.P., Wisely, G.B., Ward, P.

Description: human PXR LBD bound to GSK003
[[Category: Unreleased Structures]]
[[Category: Williams, S.P]]
[[Category: Wisely, G.B]]
[[Category: Ward, P]]