8k6l - Revision history

OCA at 11:20, 14 March 2024

OCA — Thu, 14 Mar 2024 11:20:03 GMT

←Older revision		Revision as of 11:20, 14 March 2024
Line 12:		Line 12:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/SO1B1_HUMAN SO1B1_HUMAN] Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:12196548, PubMed:11159893, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15970799, PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16627748, PubMed:16624871). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463).<ref>PMID:10358072</ref> <ref>PMID:10601278</ref> <ref>PMID:10873595</ref> <ref>PMID:11159893</ref> <ref>PMID:12196548</ref> <ref>PMID:12568656</ref> <ref>PMID:15159445</ref> <ref>PMID:15970799</ref> <ref>PMID:16624871</ref> <ref>PMID:16627748</ref> <ref>PMID:17412826</ref> <ref>PMID:19129463</ref> <ref>PMID:22232210</ref> <ref>PMID:23243220</ref> <ref>PMID:26383540</ref> <ref>PMID:26979622</ref> <ref>PMID:35307651</ref>		[https://www.uniprot.org/uniprot/SO1B1_HUMAN SO1B1_HUMAN] Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:12196548, PubMed:11159893, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15970799, PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16627748, PubMed:16624871). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463).<ref>PMID:10358072</ref> <ref>PMID:10601278</ref> <ref>PMID:10873595</ref> <ref>PMID:11159893</ref> <ref>PMID:12196548</ref> <ref>PMID:12568656</ref> <ref>PMID:15159445</ref> <ref>PMID:15970799</ref> <ref>PMID:16624871</ref> <ref>PMID:16627748</ref> <ref>PMID:17412826</ref> <ref>PMID:19129463</ref> <ref>PMID:22232210</ref> <ref>PMID:23243220</ref> <ref>PMID:26383540</ref> <ref>PMID:26979622</ref> <ref>PMID:35307651</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Members of the solute carrier organic anion transporting polypeptide (OATPs) family function as transporters for a large variety of amphipathic organic anions including endogenous metabolites and clinical drugs, such as bile salts, steroids, thyroid hormones, statins, antibiotics, antivirals, and anticancer drugs. OATP1B1 plays a vital role in transporting such substances into the liver for hepatic clearance. FDA and EMA recommend conducting in vitro testing of drug-drug interactions (DDIs) involving OATP1B1. However, the structure and working mechanism of OATPs still remains elusive. In this study, we determined cryo-EM structures of human OATP1B1 bound with representative endogenous metabolites (bilirubin and estrone-3-sulfate), a clinical drug (simeprevir), and a fluorescent indicator (2',7'-dichlorofluorescein), in both outward- and inward-open states. These structures reveal major and minor substrate binding pockets and conformational changes during transport. In combination with mutagenesis studies and molecular dynamics simulations, our work comprehensively elucidates the transport mechanism of OATP1B1 and provides the structural basis for DDI predictions involving OATP1B1, which will greatly promote our understanding of OATPs.
-
-	Cryo-EM structures of human organic anion transporting polypeptide OATP1B1.,Shan Z, Yang X, Liu H, Yuan Y, Xiao Y, Nan J, Zhang W, Song W, Wang J, Wei F, Zhang Y Cell Res. 2023 Dec;33(12):940-951. doi: 10.1038/s41422-023-00870-8. Epub 2023 Sep , 6. PMID:37674011<ref>PMID:37674011</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 8k6l" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 12:33, 20 December 2023

OCA — Wed, 20 Dec 2023 12:33:33 GMT

←Older revision		Revision as of 12:33, 20 December 2023
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 8k6l is ~~ON HOLD until Paper~~ Publication	+	==Cryo-EM structure of human OATP1B1 in complex with DCF==
		+	<StructureSection load='8k6l' size='340' side='right'caption='[[8k6l]], [[Resolution\|resolution]] 2.92Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8k6l]] 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=8K6L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8K6L FirstGlance]. <br>
		+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution\|Resolution]] 2.92Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IOQ:2,7-bis(chloranyl)-3,6-bis(oxidanyl)spiro[2-benzofuran-3,9-xanthene]-1-one'>IOQ</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=8k6l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8k6l OCA], [https://pdbe.org/8k6l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8k6l RCSB], [https://www.ebi.ac.uk/pdbsum/8k6l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8k6l ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/SO1B1_HUMAN SO1B1_HUMAN] Prediction of statin toxicity;Rotor syndrome. The disease is caused by variants affecting the gene represented in this entry.
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/SO1B1_HUMAN SO1B1_HUMAN] Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:12196548, PubMed:11159893, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15970799, PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16627748, PubMed:16624871). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463).<ref>PMID:10358072</ref> <ref>PMID:10601278</ref> <ref>PMID:10873595</ref> <ref>PMID:11159893</ref> <ref>PMID:12196548</ref> <ref>PMID:12568656</ref> <ref>PMID:15159445</ref> <ref>PMID:15970799</ref> <ref>PMID:16624871</ref> <ref>PMID:16627748</ref> <ref>PMID:17412826</ref> <ref>PMID:19129463</ref> <ref>PMID:22232210</ref> <ref>PMID:23243220</ref> <ref>PMID:26383540</ref> <ref>PMID:26979622</ref> <ref>PMID:35307651</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Members of the solute carrier organic anion transporting polypeptide (OATPs) family function as transporters for a large variety of amphipathic organic anions including endogenous metabolites and clinical drugs, such as bile salts, steroids, thyroid hormones, statins, antibiotics, antivirals, and anticancer drugs. OATP1B1 plays a vital role in transporting such substances into the liver for hepatic clearance. FDA and EMA recommend conducting in vitro testing of drug-drug interactions (DDIs) involving OATP1B1. However, the structure and working mechanism of OATPs still remains elusive. In this study, we determined cryo-EM structures of human OATP1B1 bound with representative endogenous metabolites (bilirubin and estrone-3-sulfate), a clinical drug (simeprevir), and a fluorescent indicator (2',7'-dichlorofluorescein), in both outward- and inward-open states. These structures reveal major and minor substrate binding pockets and conformational changes during transport. In combination with mutagenesis studies and molecular dynamics simulations, our work comprehensively elucidates the transport mechanism of OATP1B1 and provides the structural basis for DDI predictions involving OATP1B1, which will greatly promote our understanding of OATPs.

-	~~Authors~~:	+	Cryo-EM structures of human organic anion transporting polypeptide OATP1B1.,Shan Z, Yang X, Liu H, Yuan Y, Xiao Y, Nan J, Zhang W, Song W, Wang J, Wei F, Zhang Y Cell Res. 2023 Dec;33(12):940-951. doi: 10.1038/s41422-023-00870-8. Epub 2023 Sep , 6. PMID:37674011<ref>PMID:37674011</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 8k6l" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Shan Z]]
		+	[[Category: Yang X]]
		+	[[Category: Zhang Y]]

OCA at 03:52, 9 August 2023

OCA — Wed, 09 Aug 2023 03:52:53 GMT

←Older revision		Revision as of 03:52, 9 August 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8k6l is ON HOLD	+	The entry 8k6l is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "8k6l" [edit=sysop:move=sysop]

OCA — Wed, 02 Aug 2023 08:58:21 GMT

Protected "8k6l" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:58, 2 August 2023

OCA: New page: '''Unreleased structure''' The entry 8k6l is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 02 Aug 2023 08:58:20 GMT

New page: '''Unreleased structure''' The entry 8k6l is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 8k6l is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]