6da3 - Revision history

OCA at 15:20, 4 October 2023

2023-10-04T15:20:39Z

←Older revision		Revision as of 15:20, 4 October 2023
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	<StructureSection load='6da3' size='340' side='right'caption='[[6da3]], [[Resolution\|resolution]] 2.37Å' scene=''>		<StructureSection load='6da3' size='340' side='right'caption='[[6da3]], [[Resolution\|resolution]] 2.37Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6da3]] is a 1 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=6DA3 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6DA3 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6da3]] 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=6DA3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DA3 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G0D:tert-butyl+[(2R)-1-{[(2R)-1-oxo-3-phenyl-1-{[(pyridin-3-yl)methyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]carbamate'>G0D</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</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]] 2.37Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">CYP3A4, CYP3A3 ([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=G0D:tert-butyl+[(2R)-1-{[(2R)-1-oxo-3-phenyl-1-{[(pyridin-3-yl)methyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]carbamate'>G0D</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6da3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6da3 OCA], [~~http~~://pdbe.org/6da3 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6da3 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6da3 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6da3 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=6da3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6da3 OCA], [https://pdbe.org/6da3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6da3 RCSB], [https://www.ebi.ac.uk/pdbsum/6da3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6da3 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/CP3A4_HUMAN CP3A4_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 performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.<ref>PMID:11159812</ref>	+	[https://www.uniprot.org/uniprot/CP3A4_HUMAN CP3A4_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 performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.<ref>PMID:11159812</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Sevrioukova~~, I F]]~~	+	[[Category: Sevrioukova IF]]
-	~~[[Category: Oxidoreductase]]~~	+
-	~~[[Category: Oxidoreductase-oxidoreductase inhibitor complex~~]]	+

OCA at 06:08, 12 June 2019

2019-06-12T06:08:22Z

←Older revision		Revision as of 06:08, 12 June 2019
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	</div>		</div>
	<div class="pdbe-citations 6da3" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6da3" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Cytochrome P450 3D structures\|Cytochrome P450 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 09:07, 1 May 2019

2019-05-01T09:07:04Z

←Older revision		Revision as of 09:07, 1 May 2019
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	<StructureSection load='6da3' size='340' side='right'caption='[[6da3]], [[Resolution\|resolution]] 2.37Å' scene=''>		<StructureSection load='6da3' size='340' side='right'caption='[[6da3]], [[Resolution\|resolution]] 2.37Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6da3]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DA3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DA3 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6da3]] is a 1 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=6DA3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DA3 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G0D:tert-butyl+[(2R)-1-{[(2R)-1-oxo-3-phenyl-1-{[(pyridin-3-yl)methyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]carbamate'>G0D</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G0D:tert-butyl+[(2R)-1-{[(2R)-1-oxo-3-phenyl-1-{[(pyridin-3-yl)methyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]carbamate'>G0D</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">CYP3A4, CYP3A3 ([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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6da3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6da3 OCA], [http://pdbe.org/6da3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6da3 RCSB], [http://www.ebi.ac.uk/pdbsum/6da3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6da3 ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6da3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6da3 OCA], [http://pdbe.org/6da3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6da3 RCSB], [http://www.ebi.ac.uk/pdbsum/6da3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6da3 ProSAT]</span></td></tr>
	</table>		</table>
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Sevrioukova, I F]]		[[Category: Sevrioukova, I F]]
	[[Category: Oxidoreductase]]		[[Category: Oxidoreductase]]
	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]		[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

OCA at 06:52, 3 April 2019

2019-04-03T06:52:18Z

←Older revision		Revision as of 06:52, 3 April 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6da3 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Human CYP3A4 bound to an inhibitor==
		+	<StructureSection load='6da3' size='340' side='right'caption='[[6da3]], [[Resolution\|resolution]] 2.37Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6da3]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DA3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DA3 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G0D:tert-butyl+[(2R)-1-{[(2R)-1-oxo-3-phenyl-1-{[(pyridin-3-yl)methyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]carbamate'>G0D</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6da3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6da3 OCA], [http://pdbe.org/6da3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6da3 RCSB], [http://www.ebi.ac.uk/pdbsum/6da3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6da3 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/CP3A4_HUMAN CP3A4_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 performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.<ref>PMID:11159812</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	In a continuing effort to identify structural attributes required for strong binding and potent inhibition of human drug-metabolizing CYP3A4, we designed ten ritonavir-like analogs differing in the side-group stereochemistry, backbone atomic composition, and head-group spacing. All analogs had pyridine and tert-butyloxycarbonyl (Boc) as the heme-ligating and tail groups, respectively, phenyl side-groups, and either a methyl- or ethyl-pyridyl linker. Each linker subseries had S/R, R/S, R/R and S/S side-group conformers (4a-d and 4e-h, respectively), and one S/S stereoisomer with the backbone S-to-N-heteroatom substitution (6a and 6b). To elucidate structure-activity relationships, ligand-dependent changes in optical spectra, dissociation constant (Ks), inhibitory potency (IC50), thermostability, and heme ligation and reduction kinetics were analyzed. Comparison of the subseries and individual compounds showed that CYP3A4 only weakly discriminates between side-group configurations, associates more tightly with the pyridyl-ethyl-linker analogs, and strongly disfavors the N-containing backbone. Ks and IC50 for the pyridyl-ethyl R/R conformer, 4g, were the lowest and close to those for ritonavir: 0.04 and 0.31 microM versus 0.02 and 0.13 microM, respectively. Determination of the X-ray structures of the inhibitory complexes was critical for experimental data interpretation, especially for the uniquely oriented 4a and 4e. Based on structural analysis we conclude that, for this series of analogs, the ligand-mediated interactions near the heme are dominant and define the binding mode, and that fine-tuning of these interactions, as well as the backbone spacing could further improve the affinity and inhibitory strength.

-	~~Authors~~:	+	Structure-activity relationships of rationally designed ritonavir analogs: Impact of side-group stereochemistry, head-group spacing, and backbone composition on the interaction with CYP3A4.,Samuels ER, Sevrioukova I Biochemistry. 2019 Mar 26. doi: 10.1021/acs.biochem.9b00156. PMID:30912932<ref>PMID:30912932</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6da3" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Sevrioukova, I F]]
		+	[[Category: Oxidoreductase]]
		+	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

OCA at 04:03, 16 May 2018

2018-05-16T04:03:05Z

←Older revision		Revision as of 04:03, 16 May 2018
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6da3 is ON HOLD	+	The entry 6da3 is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "6da3" [edit=sysop:move=sysop]

2018-05-09T04:54:35Z

Protected "6da3" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:54, 9 May 2018

OCA: New page: '''Unreleased structure''' The entry 6da3 is ON HOLD Authors: Description: Category: Unreleased Structures

2018-05-09T04:54:34Z

New page: '''Unreleased structure''' The entry 6da3 is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6da3 is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]