OCA at 06:00, 11 October 2023

2023-10-11T06:00:42Z

←Older revision		Revision as of 06:00, 11 October 2023
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-	'''Unreleased structure'''

-	~~The entry~~ 8spd is ~~ON HOLD until Paper~~ Publication	+	==Cytochrome P450 (CYP) 3A4 crystallized with clotrimazole==
		+	<StructureSection load='8spd' size='340' side='right'caption='[[8spd]], [[Resolution\|resolution]] 2.90Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8spd]] 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=8SPD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SPD FirstGlance]. <br>
		+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.9Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL6:1-[(2-CHLOROPHENYL)(DIPHENYL)METHYL]-1H-IMIDAZOLE'>CL6</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'>[https://proteopedia.org/fgij/fg.htm?mol=8spd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8spd OCA], [https://pdbe.org/8spd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8spd RCSB], [https://www.ebi.ac.uk/pdbsum/8spd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8spd ProSAT]</span></td></tr>
		+	</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 ==
		+	Cytochrome P450s CYP3A5 and CYP3A4 exhibit differential plasticity that underlies differences in drug metabolism and drug-drug interactions. To extend previous studies, CYP3A4 and CYP3A5 were co-crystallized with clotrimazole, a compact ligand that binds to the heme iron in catalytic center of the active site. Binding studies indicate that clotrimazole exhibits tight binding to CYP3A5 with a Kd of<0.01 microM like that of CYP3A4. A single clotrimazole is bound to the heme iron in CYP3A4 that triggers expansion of active site cavity that reflects a loss of aromatic interactions between phenylalanine sidechains in the distal active site and increased conformational entropy for the F-F' connector due to reorientation of Phe-304 to accommodate clotrimazole. In contrast to CYP3A4, the CYP3A5 Phe-304 exhibits an induced fit along with Phe-213 to form edge-to-face aromatic interactions with heme bound clotrimazole. These aromatic interactions between aromatic amino acids propagate by induced fits with a second clotrimazole residing in the distal active site and a third clotrimazole bound in an expanded entrance channel as well as between the three clotrimazoles. The large, expanded entrance channel surrounded by the C-terminal loop and the F' and A' helices in CYP3A5 suggests conformational selection for the binding of clotrimazole due to its large girth, which may also cause the entrance channel to remain open after the binding of the first clotrimazole to the heme iron. The additional binding sites suggest a path for sequential binding of one molecule to reach and bind to the heme iron. . Significance Statement Clotrimazole binds to the heme iron of CYP3A5 and 3A4. In CYP3A5, two clotrimazoles also bind in the distal active site and in an expanded entrance channel. Aromatic interactions between clotrimazoles and phenylalanine sidechains including Phe-304 indicate induced fits for each clotrimazole. In contrast to CYP3A5, displacement of the CYP3A4 Phe-304 rotamer by clotrimazole leads to extensive disruption of phenylalanine interactions that limit the space above the heme, to an expanded active site cavity, and to increased CYP3A4 conformational heterogeneity.

-	~~Authors~~:	+	Differential Effects of Clotrimazole on X-Ray Crystal Structures of Human Cytochrome P450 (CYP) 3A5 and 3A4.,Hsu MH, Johnson EF Drug Metab Dispos. 2023 Sep 28:DMD-AR-2023-001464. doi: 10.1124/dmd.123.001464. PMID:37770228<ref>PMID:37770228</ref>

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

OCA at 04:26, 7 June 2023

2023-06-07T04:26:39Z

←Older revision		Revision as of 04:26, 7 June 2023
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	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors:		Authors:

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

2023-05-10T05:24:37Z

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

←Older revision

Revision as of 05:24, 10 May 2023

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

2023-05-10T05:24:36Z

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

New page

'''Unreleased structure'''

The entry 8spd is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]

8spd - Revision history

OCA at 06:00, 11 October 2023

OCA at 04:26, 7 June 2023

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

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