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| | <StructureSection load='5jai' size='340' side='right'caption='[[5jai]], [[Resolution|resolution]] 1.90Å' scene=''> | | <StructureSection load='5jai' size='340' side='right'caption='[[5jai]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5jai]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_pestis"_(lehmann_and_neumann_1896)_migula_1900 "bacillus pestis" (lehmann and neumann 1896) migula 1900]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JAI OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5JAI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5jai]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Yersinia_pestis Yersinia pestis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JAI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JAI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NAI:1,4-DIHYDRONICOTINAMIDE+ADENINE+DINUCLEOTIDE'>NAI</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]] 1.9Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">fabV, YPO4104, y4119, YP_4011 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=632 "Bacillus pestis" (Lehmann and Neumann 1896) Migula 1900])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NAI:1,4-DIHYDRONICOTINAMIDE+ADENINE+DINUCLEOTIDE'>NAI</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Enoyl-[acyl-carrier-protein]_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.9 1.3.1.9] </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=5jai FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jai OCA], [https://pdbe.org/5jai PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jai RCSB], [https://www.ebi.ac.uk/pdbsum/5jai PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jai ProSAT]</span></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=5jai FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jai OCA], [http://pdbe.org/5jai PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5jai RCSB], [http://www.ebi.ac.uk/pdbsum/5jai PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5jai ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FABV_YERPE FABV_YERPE]] Involved in the final reduction of the elongation cycle of fatty acid synthesis (FAS II). Catalyzes the reduction of a carbon-carbon double bond in an enoyl moiety that is covalently linked to an acyl carrier protein (ACP).<ref>PMID:22244758</ref> | + | [https://www.uniprot.org/uniprot/FABV_YERPE FABV_YERPE] Involved in the final reduction of the elongation cycle of fatty acid synthesis (FAS II). Catalyzes the reduction of a carbon-carbon double bond in an enoyl moiety that is covalently linked to an acyl carrier protein (ACP).<ref>PMID:22244758</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: HIrschbeck, M]] | + | [[Category: Yersinia pestis]] |
| - | [[Category: Kisker, C]] | + | [[Category: HIrschbeck M]] |
| - | [[Category: Kuper, J]] | + | [[Category: Kisker C]] |
| - | [[Category: Pschibul, A]] | + | [[Category: Kuper J]] |
| - | [[Category: Fatty acid biosynthesis fabv]]
| + | [[Category: Pschibul A]] |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Function
FABV_YERPE Involved in the final reduction of the elongation cycle of fatty acid synthesis (FAS II). Catalyzes the reduction of a carbon-carbon double bond in an enoyl moiety that is covalently linked to an acyl carrier protein (ACP).[1]
Publication Abstract from PubMed
The enoyl-ACP reductase (ENR) catalyzes the last reaction in the elongation cycle of the bacterial type II fatty acid biosynthesis (FAS-II) pathway. While the FabI ENR is a well-validated drug target in organisms such as Mycobacterium tuberculosis and Staphylococcus aureus, alternate ENR isoforms have been discovered in other pathogens, including the FabV enzyme that is the sole ENR in Yersinia pestis (ypFabV). Previously, we showed that the prototypical ENR inhibitor triclosan was a poor inhibitor of ypFabV and that inhibitors based on the 2-pyridone scaffold were more potent [Hirschbeck, M. (2012) Structure 20 (1), 89-100]. These studies were performed with the T276S FabV variant. In the work presented here, we describe a detailed examination of the mechanism and inhibition of wild-type ypFabV and the T276S variant. The T276S mutation significantly reduces the affinity of diphenyl ether inhibitors for ypFabV (20-fold --> 100-fold). In addition, while T276S ypFabV generally displays an affinity for 2-pyridone inhibitors higher than that of the wild-type enzyme, the 4-pyridone scaffold yields compounds with similar affinity for both wild-type and T276S ypFabV. T276 is located at the N-terminus of the helical substrate-binding loop, and structural studies coupled with site-directed mutagenesis reveal that alterations in this residue modulate the size of the active site portal. Subsequently, we were able to probe the mechanism of time-dependent inhibition in this enzyme family by extending the inhibition studies to include P142W ypFabV, a mutation that results in a gain of slow-onset inhibition for the 4-pyridone PT156.
Selectivity of Pyridone- and Diphenyl Ether-Based Inhibitors for the Yersinia pestis FabV Enoyl-ACP Reductase.,Neckles C, Pschibul A, Lai CT, Hirschbeck M, Kuper J, Davoodi S, Zou J, Liu N, Pan P, Shah S, Daryaee F, Bommineni GR, Lai C, Simmerling C, Kisker C, Tonge PJ Biochemistry. 2016 May 31;55(21):2992-3006. doi: 10.1021/acs.biochem.5b01301., Epub 2016 May 17. PMID:27136302[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hirschbeck MW, Kuper J, Lu H, Liu N, Neckles C, Shah S, Wagner S, Sotriffer CA, Tonge PJ, Kisker C. Structure of the Yersinia pestis FabV enoyl-ACP reductase and its interaction with two 2-pyridone inhibitors. Structure. 2012 Jan 11;20(1):89-100. PMID:22244758 doi:10.1016/j.str.2011.07.019
- ↑ Neckles C, Pschibul A, Lai CT, Hirschbeck M, Kuper J, Davoodi S, Zou J, Liu N, Pan P, Shah S, Daryaee F, Bommineni GR, Lai C, Simmerling C, Kisker C, Tonge PJ. Selectivity of Pyridone- and Diphenyl Ether-Based Inhibitors for the Yersinia pestis FabV Enoyl-ACP Reductase. Biochemistry. 2016 May 31;55(21):2992-3006. doi: 10.1021/acs.biochem.5b01301., Epub 2016 May 17. PMID:27136302 doi:http://dx.doi.org/10.1021/acs.biochem.5b01301
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