6vlt - Revision history

OCA at 14:38, 6 March 2024

2024-03-06T14:38:18Z

←Older revision		Revision as of 14:38, 6 March 2024
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	<StructureSection load='6vlt' size='340' side='right'caption='[[6vlt]], [[Resolution\|resolution]] 3.12Å' scene=''>		<StructureSection load='6vlt' size='340' side='right'caption='[[6vlt]], [[Resolution\|resolution]] 3.12Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6vlt]] is a 8 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VLT OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6VLT FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6vlt]] is a 8 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=6VLT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VLT FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CM5:5-CYCLOHEXYL-1-PENTYL-BETA-D-MALTOSIDE'>CM5</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=LSN:[2-butyl-5-chloranyl-3-[[4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol'>LSN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 3.12Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">CYP2C9, CYP2C10 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])~~</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CM5:5-CYCLOHEXYL-1-PENTYL-BETA-D-MALTOSIDE'>CM5</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=LSN:[2-butyl-5-chloranyl-3-[[4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol'>LSN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=6vlt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vlt OCA], [~~http~~://pdbe.org/6vlt PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6vlt RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6vlt PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6vlt 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=6vlt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vlt OCA], [https://pdbe.org/6vlt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vlt RCSB], [https://www.ebi.ac.uk/pdbsum/6vlt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vlt ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/CP2C9_HUMAN CP2C9_HUMAN]] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.	+	[https://www.uniprot.org/uniprot/CP2C9_HUMAN CP2C9_HUMAN] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	The human cytochrome P450 2C9 (CYP2C9) plays a crucial role in the metabolic clearance of a wide range of clinical therapeutics. The 2 allele is a prevalent genetic variation in CYP2C9 that is found in various populations. A marked reduction of catalytic activity towards many important drug substrates has been demonstrated by CYP2C92, which represents an amino acid variation at position 144 from arginine to cysteine. The crystal structure of CYP2C92 in complex with an anti-hypertensive drug losartan was solved using X-ray crystallography at 3.1 A resolution. The Arg144Cys variation in the 2 complex disrupts the hydrogen bonding interactions that were observed between the side chain of arginine and neighboring residues in the losartan complex of CYP2C9 and the wild-type (WT) ligand-free structure. The conformation of several secondary structural elements is affected, thereby altering the binding and orientation of drug and important amino acid side chains in the distal active site cavity. The new structure revealed distinct interactions of losartan in the compact active site of CYP2C92 and differed in occupancy at the other binding sites previously identified in the WT-losartan complex. Furthermore, the binding studies in solution using losartan illustrated lower activity of the CYP2C92 compared to the WT. Together, the findings yield valuable insights into the decreased hydroxylation activity of losartan in patients carrying CYP2C92 allele, and provide a useful framework to investigate the effect of a single nucleotide polymorphism that leads to altered metabolism of diverse drug substrates. Significance Statement The 2 allele of the human drug metabolizing enzyme CYP2C9 is found in different populations and results in significantly reduced activity towards various drug substrates. How the CYP2C9*2 variant induces altered drug metabolism is poorly understood given that the Arg144Cys variation is located far away from the active site. This work yield insight into the effect of distal variation using multitude of techniques that include X-ray crystallography, isothermal titration calorimetry, enzymatic characterization and computational studies.	+
-		+
-	Structure of cytochrome P450 2C9*2 in complex with an anti-hypertensive drug losartan: Insights into the effect of genetic polymorphism.,Parikh SJ, Evans CM, Obi JO, Zhang Q, Maekawa K, Glass KC, Shah MB Mol Pharmacol. 2020 Sep 16. pii: molpharm.120.000042. doi:, 10.1124/molpharm.120.000042. PMID:32938720<ref>PMID:32938720</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 6vlt" style="background-color:#fffaf0;"></div>~~	+
-	~~== References ==~~	+
-	~~<references/>~~	+
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Shah~~, M B]]~~	+	[[Category: Shah MB]]
-	~~[[Category: Cyp2c9 r144c]]~~	+
-	~~[[Category: Cyp2c9*2]]~~	+
-	~~[[Category: Oxidoreductase~~]]	+

OCA at 20:49, 28 October 2020

2020-10-28T20:49:07Z

←Older revision		Revision as of 20:49, 28 October 2020
Line 1:		Line 1:

	==Crystal Structure of Human P450 2C9*2 Genetic Variant in Complex with Losartan==		==Crystal Structure of Human P450 2C9*2 Genetic Variant in Complex with Losartan==
-	<StructureSection load='6vlt' size='340' side='right'caption='[[6vlt]]' scene=''>	+	<StructureSection load='6vlt' size='340' side='right'caption='[[6vlt]], [[Resolution\|resolution]] 3.12Å' 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=6VLT OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6VLT FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6vlt]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VLT OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6VLT FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6vlt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vlt OCA], [http://pdbe.org/6vlt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vlt RCSB], [http://www.ebi.ac.uk/pdbsum/6vlt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vlt 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=CM5:5-CYCLOHEXYL-1-PENTYL-BETA-D-MALTOSIDE'>CM5</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=LSN:[2-butyl-5-chloranyl-3-[[4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol'>LSN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">CYP2C9, CYP2C10 ([http://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'>[http://proteopedia.org/fgij/fg.htm?mol=6vlt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vlt OCA], [http://pdbe.org/6vlt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vlt RCSB], [http://www.ebi.ac.uk/pdbsum/6vlt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vlt ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/CP2C9_HUMAN CP2C9_HUMAN]] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The human cytochrome P450 2C9 (CYP2C9) plays a crucial role in the metabolic clearance of a wide range of clinical therapeutics. The 2 allele is a prevalent genetic variation in CYP2C9 that is found in various populations. A marked reduction of catalytic activity towards many important drug substrates has been demonstrated by CYP2C92, which represents an amino acid variation at position 144 from arginine to cysteine. The crystal structure of CYP2C92 in complex with an anti-hypertensive drug losartan was solved using X-ray crystallography at 3.1 A resolution. The Arg144Cys variation in the 2 complex disrupts the hydrogen bonding interactions that were observed between the side chain of arginine and neighboring residues in the losartan complex of CYP2C9 and the wild-type (WT) ligand-free structure. The conformation of several secondary structural elements is affected, thereby altering the binding and orientation of drug and important amino acid side chains in the distal active site cavity. The new structure revealed distinct interactions of losartan in the compact active site of CYP2C92 and differed in occupancy at the other binding sites previously identified in the WT-losartan complex. Furthermore, the binding studies in solution using losartan illustrated lower activity of the CYP2C92 compared to the WT. Together, the findings yield valuable insights into the decreased hydroxylation activity of losartan in patients carrying CYP2C92 allele, and provide a useful framework to investigate the effect of a single nucleotide polymorphism that leads to altered metabolism of diverse drug substrates. Significance Statement The 2 allele of the human drug metabolizing enzyme CYP2C9 is found in different populations and results in significantly reduced activity towards various drug substrates. How the CYP2C9*2 variant induces altered drug metabolism is poorly understood given that the Arg144Cys variation is located far away from the active site. This work yield insight into the effect of distal variation using multitude of techniques that include X-ray crystallography, isothermal titration calorimetry, enzymatic characterization and computational studies.
		+
		+	Structure of cytochrome P450 2C9*2 in complex with an anti-hypertensive drug losartan: Insights into the effect of genetic polymorphism.,Parikh SJ, Evans CM, Obi JO, Zhang Q, Maekawa K, Glass KC, Shah MB Mol Pharmacol. 2020 Sep 16. pii: molpharm.120.000042. doi:, 10.1124/molpharm.120.000042. PMID:32938720<ref>PMID:32938720</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6vlt" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Shah MB]]	+	[[Category: Shah, M B]]
		+	[[Category: Cyp2c9 r144c]]
		+	[[Category: Cyp2c9*2]]
		+	[[Category: Oxidoreductase]]

OCA at 07:09, 30 September 2020

2020-09-30T07:09:09Z

←Older revision		Revision as of 07:09, 30 September 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6vlt ~~is ON HOLD until Paper Publication~~	+	==Crystal Structure of Human P450 2C9*2 Genetic Variant in Complex with Losartan==
-		+	<StructureSection load='6vlt' size='340' side='right'caption='[[6vlt]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VLT OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6VLT FirstGlance]. <br>
-	~~Description~~:	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6vlt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vlt OCA], [http://pdbe.org/6vlt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vlt RCSB], [http://www.ebi.ac.uk/pdbsum/6vlt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vlt ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Shah MB]]

OCA at 05:17, 19 February 2020

2020-02-19T05:17:09Z

←Older revision		Revision as of 05:17, 19 February 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6vlt is ON HOLD	+	The entry 6vlt is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "6vlt" [edit=sysop:move=sysop]

2020-02-05T06:16:27Z

Protected "6vlt" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:16, 5 February 2020

OCA: New page: '''Unreleased structure''' The entry 6vlt is ON HOLD Authors: Description: Category: Unreleased Structures

2020-02-05T06:16:26Z

New page: '''Unreleased structure''' The entry 6vlt is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6vlt is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]