View source for 6h1o


==Structure of the BM3 heme domain in complex with voriconazole==
<StructureSection load='6h1o' size='340' side='right' caption='[[6h1o]], [[Resolution|resolution]] 1.73&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6h1o]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6H1O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6H1O FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=VOR:VORICONAZOLE'>VOR</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=6h1o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h1o OCA], [http://pdbe.org/6h1o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6h1o RCSB], [http://www.ebi.ac.uk/pdbsum/6h1o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6h1o ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/CPXB_BACMB CPXB_BACMB]] Functions as a fatty acid monooxygenase (PubMed:3106359, PubMed:1727637, PubMed:16566047, PubMed:7578081, PubMed:11695892, PubMed:14653735, PubMed:16403573, PubMed:18004886, PubMed:17077084, PubMed:17868686, PubMed:18298086, PubMed:18619466, PubMed:18721129, PubMed:19492389, PubMed:20180779, PubMed:21110374, PubMed:21875028). Catalyzes hydroxylation of fatty acids at omega-1, omega-2 and omega-3 positions (PubMed:1727637, PubMed:21875028). Shows activity toward medium and long-chain fatty acids, with optimum chain lengths of 12, 14 and 16 carbons (lauric, myristic, and palmitic acids). Able to metabolize some of these primary metabolites to secondary and tertiary products (PubMed:1727637). Marginal activity towards short chain lengths of 8-10 carbons (PubMed:1727637, PubMed:18619466). Hydroxylates highly branched fatty acids, which play an essential role in membrane fluidity regulation (PubMed:16566047). Also displays a NADPH-dependent reductase activity in the C-terminal domain, which allows electron transfer from NADPH to the heme iron of the cytochrome P450 N-terminal domain (PubMed:3106359, PubMed:1727637, PubMed:16566047, PubMed:7578081, PubMed:11695892, PubMed:14653735, PubMed:16403573, PubMed:18004886, PubMed:17077084, PubMed:17868686, PubMed:18298086, PubMed:18619466, PubMed:18721129, PubMed:19492389, PubMed:20180779, PubMed:21110374, PubMed:21875028). Involved in inactivation of quorum sensing signals of other competing bacteria by oxidazing efficiently acyl homoserine lactones (AHLs), molecules involved in quorum sensing signaling pathways, and their lactonolysis products acyl homoserines (AHs) (PubMed:18020460).<ref>PMID:11695892</ref> <ref>PMID:14653735</ref> <ref>PMID:16403573</ref> <ref>PMID:16566047</ref> <ref>PMID:17077084</ref> <ref>PMID:1727637</ref> <ref>PMID:17868686</ref> <ref>PMID:18004886</ref> <ref>PMID:18020460</ref> <ref>PMID:18298086</ref> <ref>PMID:18619466</ref> <ref>PMID:18721129</ref> <ref>PMID:19492389</ref> <ref>PMID:20180779</ref> <ref>PMID:21110374</ref> <ref>PMID:21875028</ref> <ref>PMID:3106359</ref> <ref>PMID:7578081</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Flavocytochrome P450 BM3 is a natural fusion protein constructed of cytochrome P450 and NADPH-cytochrome P450 reductase domains. P450 BM3 binds and oxidizes several mid- to long-chain fatty acids, typically hydroxylating these lipids at the omega-1, omega-2 and omega-3 positions. However, protein engineering has led to variants of this enzyme that are able to bind and oxidize diverse compounds, including steroids, terpenes and various human drugs. The wild-type P450 BM3 enzyme binds inefficiently to many azole antifungal drugs. However, we show that the BM3 A82F/F87V double mutant (DM) variant binds substantially tighter to numerous azole drugs than does the wild-type BM3, and that their binding occurs with more extensive heme spectral shifts indicative of complete binding of several azoles to the BM3 DM heme iron. We report here the first crystal structures of P450 BM3 bound to azole antifungal drugs - with the BM3 DM heme domain bound to the imidazole drugs clotrimazole and tioconazole, and to the triazole drugs fluconazole and voriconazole. This is the first report of any protein structure bound to the azole drug tioconazole, as well as the first example of voriconazole heme iron ligation through a pyrimidine nitrogen from its 5-fluoropyrimidine ring.

Novel insights into P450 BM3 interactions with FDA-approved antifungal azole drugs.,Jeffreys LN, Poddar H, Golovanova M, Levy CW, Girvan HM, McLean KJ, Voice MW, Leys D, Munro AW Sci Rep. 2019 Feb 7;9(1):1577. doi: 10.1038/s41598-018-37330-y. PMID:30733479<ref>PMID:30733479</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6h1o" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Jeffreys, L N]]
[[Category: Leys, D]]
[[Category: Munro, A W.M]]
[[Category: Azole inhibitor]]
[[Category: Heme ligation]]
[[Category: Oxidoreductase]]
[[Category: P450]]
[[Category: P450 bm3]]