4key - Revision history

OCA at 11:19, 13 August 2026

2026-08-13T11:19:42Z

← Older revision		Revision as of 11:19, 13 August 2026
Line 9:		Line 9:
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/CPXB_PRIM2 CPXB_PRIM2] 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>		[https://www.uniprot.org/uniprot/CPXB_PRIM2 CPXB_PRIM2] Functions as a fatty acid monooxygenase (PubMed:11695892, PubMed:14653735, PubMed:16403573, PubMed:16566047, PubMed:17077084, PubMed:1727637, PubMed:17868686, PubMed:18004886, PubMed:18298086, PubMed:18619466, PubMed:18721129, PubMed:19492389, PubMed:20180779, PubMed:21110374, PubMed:21875028, PubMed:3106359, PubMed:7578081). 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:11695892, PubMed:14653735, PubMed:16403573, PubMed:16566047, PubMed:17077084, PubMed:1727637, PubMed:17868686, PubMed:18004886, PubMed:18298086, PubMed:18619466, PubMed:18721129, PubMed:19492389, PubMed:20180779, PubMed:21110374, PubMed:21875028, PubMed:3106359, PubMed:7578081). 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 ==
			Cytochrome P450 monooxygenases (P450s) have enormous potential in the production of oxychemicals, due to their unparalleled regio- and stereoselectivity. The Bacillus megaterium P450 BM3 enzyme is a key model system, with several mutants (many distant from the active site) reported to alter substrate selectivity. It has the highest reported monooxygenase activity of the P450 enzymes, and this catalytic efficiency has inspired protein engineering to enable its exploitation for biotechnologically relevant oxidations with structurally diverse substrates. However, a structural rationale is lacking to explain how these mutations have such effects in the absence of direct change to the active site architecture. Here, we provide the first crystal structures of BM3 mutants in complex with a human drug substrate, the proton pump inhibitor omeprazole. Supported by solution data, these structures reveal how mutation alters the conformational landscape and decreases the free energy barrier for transition to the substrate-bound state. Our data point to the importance of such "gatekeeper" mutations in enabling major changes in substrate recognition. We further demonstrate that these mutants catalyze the same 5-hydroxylation reaction as performed by human CYP2C19, the major human omeprazole-metabolizing P450 enzyme.

			Key Mutations Alter the Cytochrome P450 BM3 Conformational Landscape and Remove Inherent Substrate Bias.,Butler CF, Peet C, Mason AE, Voice MW, Leys D, Munro AW J Biol Chem. 2013 Aug 30;288(35):25387-99. doi: 10.1074/jbc.M113.479717. Epub, 2013 Jul 3. PMID:23828198<ref>PMID:23828198</ref>

			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>
			<div class="pdbe-citations 4key" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 12:12, 1 March 2024

2024-03-01T12:12:06Z

← Older revision		Revision as of 12:12, 1 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4key]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Priestia_megaterium Priestia megaterium]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KEY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KEY FirstGlance]. <br>		<table><tr><td colspan='2'>[[4key]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Priestia_megaterium Priestia megaterium]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KEY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KEY FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1C6:6-METHOXY-2-{[(4-METHOXY-3,5-DIMETHYLPYRIDIN-2-YL)METHYL]SULFANYL}-1H-BENZIMIDAZOLE'>1C6</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]] 2.05Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1C6:6-METHOXY-2-{[(4-METHOXY-3,5-DIMETHYLPYRIDIN-2-YL)METHYL]SULFANYL}-1H-BENZIMIDAZOLE'>1C6</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=4key FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4key OCA], [https://pdbe.org/4key PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4key RCSB], [https://www.ebi.ac.uk/pdbsum/4key PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4key 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=4key FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4key OCA], [https://pdbe.org/4key PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4key RCSB], [https://www.ebi.ac.uk/pdbsum/4key PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4key ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/CPXB_PRIM2 CPXB_PRIM2] 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>		[https://www.uniprot.org/uniprot/CPXB_PRIM2 CPXB_PRIM2] 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 ==~~
	Cytochrome P450 monooxygenases (P450s) have enormous potential in the production of oxychemicals, due to their unparalleled regio- and stereoselectivity. The Bacillus megaterium P450 BM3 enzyme is a key model system, with several mutants (many distant from the active site) reported to alter substrate selectivity. It has the highest reported monooxygenase activity of the P450 enzymes, and this catalytic efficiency has inspired protein engineering to enable its exploitation for biotechnologically relevant oxidations with structurally diverse substrates. However, a structural rationale is lacking to explain how these mutations have such effects in the absence of direct change to the active site architecture. Here, we provide the first crystal structures of BM3 mutants in complex with a human drug substrate, the proton pump inhibitor omeprazole. Supported by solution data, these structures reveal how mutation alters the conformational landscape and decreases the free energy barrier for transition to the substrate-bound state. Our data point to the importance of such "gatekeeper" mutations in enabling major changes in substrate recognition. We further demonstrate that these mutants catalyze the same 5-hydroxylation reaction as performed by human CYP2C19, the major human omeprazole-metabolizing P450 enzyme.

	Key Mutations Alter the Cytochrome P450 BM3 Conformational Landscape and Remove Inherent Substrate Bias.,Butler CF, Peet C, Mason AE, Voice MW, Leys D, Munro AW J Biol Chem. 2013 Aug 30;288(35):25387-99. doi: 10.1074/jbc.M113.479717. Epub, 2013 Jul 3. PMID:23828198<ref>PMID:23828198</ref>

	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class="pdbe-citations 4key" style="background-color:#fffaf0;"></div>~~

	==See Also==		==See Also==

OCA at 11:55, 30 November 2022

2022-11-30T11:55:00Z

← Older revision		Revision as of 11:55, 30 November 2022
Line 1:		Line 1:

	==Structure of P450 BM3 A82F F87V in complex with omeprazole==		==Structure of P450 BM3 A82F F87V in complex with omeprazole==
	<StructureSection load='4key' size='340' side='right' caption='[[4key]], [[Resolution\|resolution]] 2.05Å' scene=''>		<StructureSection load='4key' size='340' side='right'caption='[[4key]], [[Resolution\|resolution]] 2.05Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4key]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Atcc_14581 Atcc 14581~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KEY OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4KEY FirstGlance]. <br>		<table><tr><td colspan='2'>[[4key]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Priestia_megaterium Priestia megaterium]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KEY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KEY FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1C6:6-METHOXY-2-{[(4-METHOXY-3,5-DIMETHYLPYRIDIN-2-YL)METHYL]SULFANYL}-1H-BENZIMIDAZOLE'>1C6</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" id="ligandDat"><scene name='pdbligand=1C6:6-METHOXY-2-{[(4-METHOXY-3,5-DIMETHYLPYRIDIN-2-YL)METHYL]SULFANYL}-1H-BENZIMIDAZOLE'>1C6</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4kew\|4kew]], [[4kf0\|4kf0]], [[4kf2\|4kf2]]</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=4key FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4key OCA], [https://pdbe.org/4key PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4key RCSB], [https://www.ebi.ac.uk/pdbsum/4key PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4key ProSAT]</span></td></tr>
	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">cyp102A1, cyp102 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1404 ATCC 14581])~~</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=4key FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4key OCA], [~~http~~://pdbe.org/4key PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4key RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4key PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4key ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[~~[http~~://www.uniprot.org/uniprot/~~CPXB_BACME CPXB_BACME]~~] Functions as a fatty acid monooxygenase. Catalyzes hydroxylation of ~~medium and long-chain~~ fatty acids at omega-1, omega-2 and omega-3 positions, with optimum chain lengths of 12-16 carbons (lauric, myristic, and palmitic acids). ~~The~~ reductase domain ~~is required for~~ electron transfer from ~~NADP~~ to cytochrome P450.		[https://www.uniprot.org/uniprot/CPXB_PRIM2 CPXB_PRIM2] 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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 22:		Line 20:

	==See Also==		==See Also==
	*[[Cytochrome P450\|Cytochrome P450]]		*[[Cytochrome P450 3D structures\|Cytochrome P450 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Atcc 14581~~]]		[[Category: Large Structures]]
	[[Category: ~~Leys, D~~]]		[[Category: Priestia megaterium]]
	[[Category: ~~Monooxygenase]]~~		[[Category: Leys D]]
	~~[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]~~
	~~[[Category: P450 heme domain~~]]

OCA at 00:02, 5 August 2016

2016-08-05T00:02:46Z

← Older revision		Revision as of 00:02, 5 August 2016
Line 1:		Line 1:

	==Structure of P450 BM3 A82F F87V in complex with omeprazole==		==Structure of P450 BM3 A82F F87V in complex with omeprazole==
	<StructureSection load='4key' size='340' side='right' caption='[[4key]], [[Resolution\|resolution]] 2.05Å' scene=''>		<StructureSection load='4key' size='340' side='right' caption='[[4key]], [[Resolution\|resolution]] 2.05Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4key]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Bacillus_megaterium Bacillus megaterium~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KEY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KEY FirstGlance]. <br>		<table><tr><td colspan='2'>[[4key]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Atcc_14581 Atcc 14581]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KEY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KEY FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1C6:6-METHOXY-2-{[(4-METHOXY-3,5-DIMETHYLPYRIDIN-2-YL)METHYL]SULFANYL}-1H-BENZIMIDAZOLE'>1C6</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=1C6:6-METHOXY-2-{[(4-METHOXY-3,5-DIMETHYLPYRIDIN-2-YL)METHYL]SULFANYL}-1H-BENZIMIDAZOLE'>1C6</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4kew\|4kew]], [[4kf0\|4kf0]], [[4kf2\|4kf2]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4kew\|4kew]], [[4kf0\|4kf0]], [[4kf2\|4kf2]]</td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">cyp102A1, cyp102 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1404 ~~Bacillus megaterium~~])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">cyp102A1, cyp102 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1404 ATCC 14581])</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=4key FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4key OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4key RCSB], [http://www.ebi.ac.uk/pdbsum/4key PDBsum]</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=4key FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4key OCA], [http://pdbe.org/4key PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4key RCSB], [http://www.ebi.ac.uk/pdbsum/4key PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4key ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
			<div class="pdbe-citations 4key" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 25:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Bacillus megaterium~~]]		[[Category: Atcc 14581]]
	[[Category: Leys, D]]		[[Category: Leys, D]]
	[[Category: Monooxygenase]]		[[Category: Monooxygenase]]
	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]		[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
	[[Category: P450 heme domain]]		[[Category: P450 heme domain]]

OCA at 20:59, 24 December 2014

2014-12-24T20:59:39Z

← Older revision		Revision as of 20:59, 24 December 2014
Line 8:		Line 8:
	<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=4key FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4key OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4key RCSB], [http://www.ebi.ac.uk/pdbsum/4key PDBsum]</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=4key FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4key OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4key RCSB], [http://www.ebi.ac.uk/pdbsum/4key PDBsum]</span></td></tr>
	</table>		</table>
			== Function ==
			[[http://www.uniprot.org/uniprot/CPXB_BACME CPXB_BACME]] Functions as a fatty acid monooxygenase. Catalyzes hydroxylation of medium and long-chain fatty acids at omega-1, omega-2 and omega-3 positions, with optimum chain lengths of 12-16 carbons (lauric, myristic, and palmitic acids). The reductase domain is required for electron transfer from NADP to cytochrome P450.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 14:33, 21 December 2014

2014-12-21T14:33:49Z

← Older revision		Revision as of 14:33, 21 December 2014
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	~~{{STRUCTURE_4key\| PDB=4key \| SCENE= }}~~		==Structure of P450 BM3 A82F F87V in complex with omeprazole==
	===Structure of P450 BM3 A82F F87V in complex with omeprazole===		<StructureSection load='4key' size='340' side='right' caption='[[4key]], [[Resolution\|resolution]] 2.05Å' scene=''>
	{~~{ABSTRACT_PUBMED_23828198}~~}		== Structural highlights ==
			<table><tr><td colspan='2'>[[4key]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bacillus_megaterium Bacillus megaterium]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KEY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KEY FirstGlance]. <br>
			</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1C6:6-METHOXY-2-{[(4-METHOXY-3,5-DIMETHYLPYRIDIN-2-YL)METHYL]SULFANYL}-1H-BENZIMIDAZOLE'>1C6</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
			<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4kew\|4kew]], [[4kf0\|4kf0]], [[4kf2\|4kf2]]</td></tr>
			<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">cyp102A1, cyp102 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1404 Bacillus megaterium])</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=4key FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4key OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4key RCSB], [http://www.ebi.ac.uk/pdbsum/4key PDBsum]</span></td></tr>
			</table>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			Cytochrome P450 monooxygenases (P450s) have enormous potential in the production of oxychemicals, due to their unparalleled regio- and stereoselectivity. The Bacillus megaterium P450 BM3 enzyme is a key model system, with several mutants (many distant from the active site) reported to alter substrate selectivity. It has the highest reported monooxygenase activity of the P450 enzymes, and this catalytic efficiency has inspired protein engineering to enable its exploitation for biotechnologically relevant oxidations with structurally diverse substrates. However, a structural rationale is lacking to explain how these mutations have such effects in the absence of direct change to the active site architecture. Here, we provide the first crystal structures of BM3 mutants in complex with a human drug substrate, the proton pump inhibitor omeprazole. Supported by solution data, these structures reveal how mutation alters the conformational landscape and decreases the free energy barrier for transition to the substrate-bound state. Our data point to the importance of such "gatekeeper" mutations in enabling major changes in substrate recognition. We further demonstrate that these mutants catalyze the same 5-hydroxylation reaction as performed by human CYP2C19, the major human omeprazole-metabolizing P450 enzyme.

	~~==Function==~~		Key Mutations Alter the Cytochrome P450 BM3 Conformational Landscape and Remove Inherent Substrate Bias.,Butler CF, Peet C, Mason AE, Voice MW, Leys D, Munro AW J Biol Chem. 2013 Aug 30;288(35):25387-99. doi: 10.1074/jbc.M113.479717. Epub, 2013 Jul 3. PMID:23828198<ref>PMID:23828198</ref>
	~~[[http~~:/~~/www~~.~~uniprot~~.~~org/uniprot/CPXB_BACME CPXB_BACME]] Functions as a fatty acid monooxygenase~~. ~~Catalyzes hydroxylation of medium and long-chain fatty acids at omega-1~~, ~~omega-2 and omega-~~3 ~~positions, with optimum chain lengths of 12-16 carbons (lauric, myristic, and palmitic acids). The reductase domain is required for electron transfer from NADP to cytochrome P450~~.

	~~==About this Structure==~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	~~[[4key]] is~~ a ~~2 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Bacillus_megaterium Bacillus megaterium]~~. ~~Full crystallographic information is available from [http:/~~/~~oca.weizmann.ac.il/oca-bin/ocashort?id=4KEY OCA].~~		</div>

	==See Also==		==See Also==
	*[[Cytochrome P450\|Cytochrome P450]]		*[[Cytochrome P450\|Cytochrome P450]]
			== References ==
	==~~Reference~~==		<references/>
	~~<ref group="xtra">PMID:023828198</ref>~~<references ~~group="xtra"~~/><~~references~~/>		__TOC__
			</StructureSection>
	[[Category: Bacillus megaterium]]		[[Category: Bacillus megaterium]]
	[[Category: Leys, D.]]		[[Category: Leys, D]]
	[[Category: Monooxygenase]]		[[Category: Monooxygenase]]
	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]		[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
	[[Category: P450 heme domain]]		[[Category: P450 heme domain]]

OCA at 06:11, 2 October 2013

2013-10-02T06:11:09Z

← Older revision		Revision as of 06:11, 2 October 2013
Line 1:		Line 1:
	{{STRUCTURE_4key\| PDB=4key \| SCENE= }}		{{STRUCTURE_4key\| PDB=4key \| SCENE= }}
	===Structure of P450 BM3 A82F F87V in complex with omeprazole===		===Structure of P450 BM3 A82F F87V in complex with omeprazole===
			{{ABSTRACT_PUBMED_23828198}}

	==Function==		==Function==
Line 7:		Line 8:
	==About this Structure==		==About this Structure==
	[[4key]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bacillus_megaterium Bacillus megaterium]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KEY OCA].		[[4key]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bacillus_megaterium Bacillus megaterium]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KEY OCA].

			==See Also==
			*[[Cytochrome P450\|Cytochrome P450]]

			==Reference==
			<ref group="xtra">PMID:023828198</ref><references group="xtra"/><references/>
	[[Category: Bacillus megaterium]]		[[Category: Bacillus megaterium]]
	[[Category: Leys, D.]]		[[Category: Leys, D.]]

OCA at 15:54, 10 July 2013

2013-07-10T15:54:21Z

← Older revision		Revision as of 15:54, 10 July 2013
Line 1:		Line 1:
	~~'''Unreleased structure'''~~		{{STRUCTURE_4key\| PDB=4key \| SCENE= }}
			===Structure of P450 BM3 A82F F87V in complex with omeprazole===

	The ~~entry 4key~~ is ~~ON HOLD until Paper Publication~~		==Function==
			[[http://www.uniprot.org/uniprot/CPXB_BACME CPXB_BACME]] Functions as a fatty acid monooxygenase. Catalyzes hydroxylation of medium and long-chain fatty acids at omega-1, omega-2 and omega-3 positions, with optimum chain lengths of 12-16 carbons (lauric, myristic, and palmitic acids). The reductase domain is required for electron transfer from NADP to cytochrome P450.

	~~Authors~~: Leys, D.		==About this Structure==
			[[4key]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bacillus_megaterium Bacillus megaterium]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KEY OCA].
	~~Description~~: ~~Structure of~~ P450 ~~BM3 A82F F87V in complex with omeprazole~~		[[Category: Bacillus megaterium]]
			[[Category: Leys, D.]]
			[[Category: Monooxygenase]]
			[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
			[[Category: P450 heme domain]]

OCA at 11:35, 19 June 2013

2013-06-19T11:35:48Z

← Older revision		Revision as of 11:35, 19 June 2013
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 4key is ON HOLD		The entry 4key is ON HOLD until Paper Publication

	Authors: Leys, D.		Authors: Leys, D.

	Description: Structure of P450 BM3 A82F F87V in complex with omeprazole		Description: Structure of P450 BM3 A82F F87V in complex with omeprazole

OCA: Protected "4key" [edit=sysop:move=sysop]

2013-05-08T07:21:15Z

Protected "4key" [edit=sysop:move=sysop]

← Older revision	Revision as of 07:21, 8 May 2013
(No difference)