OCA at 15:32, 18 October 2023

OCA — Wed, 18 Oct 2023 15:32:29 GMT

←Older revision		Revision as of 15:32, 18 October 2023
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	==Human CYP3A4 bound to an inhibitor==		==Human CYP3A4 bound to an inhibitor==
-	<StructureSection load='7kvk' size='340' side='right'caption='[[7kvk]]' scene=''>	+	<StructureSection load='7kvk' size='340' side='right'caption='[[7kvk]], [[Resolution\|resolution]] 2.55Å' 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=7KVK OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=7KVK FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7kvk]] is a 2 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=7KVK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KVK 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=7kvk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kvk OCA], [~~http~~://pdbe.org/7kvk PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=7kvk RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/7kvk PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=7kvk ProSAT]</span></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]] 2.55Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=X7J:tert-butyl+[(2R)-1-{[(2R)-1-oxo-3-phenyl-1-{[3-(pyridin-3-yl)propyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]carbamate'>X7J</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=7kvk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kvk OCA], [https://pdbe.org/7kvk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kvk RCSB], [https://www.ebi.ac.uk/pdbsum/7kvk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kvk ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[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;">
		+	== Publication Abstract from PubMed ==
		+	Inhibition of the major human drug-metabolizing cytochrome P450 3A4 (CYP3A4) by pharmaceuticals and other xenobiotics could lead to toxicity, drug-drug interactions and other adverse effects, as well as pharmacoenhancement. Despite serious clinical implications, the structural basis and attributes required for the potent inhibition of CYP3A4 remain to be established. We utilized a rational inhibitor design to investigate the structure-activity relationships in the analogues of ritonavir, the most potent CYP3A4 inhibitor in clinical use. This study elucidated the optimal length of the head-group spacer using eleven (series V) analogues with the R(1)/R(2) side-groups as phenyls or R(1)-phenyl/R(2)-indole/naphthalene in various stereo configurations. Spectral, functional and structural characterization of the inhibitory complexes showed that a one-atom head-group linker elongation, from pyridyl-ethyl to pyridyl-propyl, was beneficial and markedly improved K(s), IC(50) and thermostability of CYP3A4. In contrast, a two-atom linker extension led to a multi-fold decrease in the binding and inhibitory strength, possibly due to spatial and/or conformational constraints. The lead compound, 3h, was among the best inhibitors designed so far and overall, the strongest binder (K(s) and IC(50) of 0.007 and 0.090 microM, respectively). 3h was the fourth structurally simpler inhibitor superior to ritonavir, which further demonstrates the power of our approach.
		+
		+	Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength.,Samuels ER, Sevrioukova IF Int J Mol Sci. 2021 Jan 16;22(2):852. doi: 10.3390/ijms22020852. PMID:33467005<ref>PMID:33467005</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7kvk" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Sevrioukova I]]		[[Category: Sevrioukova I]]

OCA at 08:15, 20 January 2021

OCA — Wed, 20 Jan 2021 08:15:14 GMT

←Older revision		Revision as of 08:15, 20 January 2021
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-	'''Unreleased structure'''

-	~~The entry~~ 7kvk ~~is ON HOLD until Paper Publication~~	+	==Human CYP3A4 bound to an inhibitor==
-		+	<StructureSection load='7kvk' size='340' side='right'caption='[[7kvk]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KVK OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7KVK 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=7kvk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kvk OCA], [http://pdbe.org/7kvk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7kvk RCSB], [http://www.ebi.ac.uk/pdbsum/7kvk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7kvk ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Sevrioukova I]]

OCA at 11:13, 16 December 2020

OCA — Wed, 16 Dec 2020 11:13:03 GMT

←Older revision		Revision as of 11:13, 16 December 2020
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7kvk is ON HOLD	+	The entry 7kvk is ON HOLD until Paper Publication

	Authors:		Authors:

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

OCA — Wed, 09 Dec 2020 05:15:24 GMT

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

←Older revision

Revision as of 05:15, 9 December 2020

OCA: New page: '''Unreleased structure''' The entry 7kvk is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 09 Dec 2020 05:15:23 GMT

New page: '''Unreleased structure''' The entry 7kvk is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7kvk is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]

7kvk - Revision history

OCA at 15:32, 18 October 2023

OCA at 08:15, 20 January 2021

OCA at 11:13, 16 December 2020

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

OCA: New page: '''Unreleased structure''' The entry 7kvk is ON HOLD Authors: Description: Category: Unreleased Structures