4fs3

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==Crystal structure of Staphylococcus aureus enoyl-ACP reductase in complex with NADP and AFN-1252==
==Crystal structure of Staphylococcus aureus enoyl-ACP reductase in complex with NADP and AFN-1252==
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<StructureSection load='4fs3' size='340' side='right' caption='[[4fs3]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
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<StructureSection load='4fs3' size='340' side='right'caption='[[4fs3]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4fs3]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Staar Staar]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FS3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FS3 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4fs3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_MRSA252 Staphylococcus aureus subsp. aureus MRSA252]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FS3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FS3 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0WD:[[(2R,3S,4R,5R)-5-(3-AMINOCARBONYL-4H-PYRIDIN-1-YL)-3,4-BIS(OXIDANYL)OXOLAN-2-YL]METHOXY-OXIDANYL-PHOSPHORYL]+[(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-4-OXIDANYL-3-PHOSPHONOOXY-OXOLAN-2-YL]METHYL+HYDROGEN+PHOSPHATE'>0WD</scene>, <scene name='pdbligand=0WE:N-METHYL-N-[(3-METHYL-1-BENZOFURAN-2-YL)METHYL]-3-(7-OXO-5,6,7,8-TETRAHYDRO-1,8-NAPHTHYRIDIN-3-YL)PROPANAMIDE'>0WE</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">fabI, SAR0978 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=282458 STAAR])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0WD:[[(2R,3S,4R,5R)-5-(3-aminocarbonyl-4H-pyridin-1-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]+[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methyl+hydrogen+phosphate'>0WD</scene>, <scene name='pdbligand=0WE:N-METHYL-N-[(3-METHYL-1-BENZOFURAN-2-YL)METHYL]-3-(7-OXO-5,6,7,8-TETRAHYDRO-1,8-NAPHTHYRIDIN-3-YL)PROPANAMIDE'>0WE</scene></td></tr>
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<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_(NADPH,_B-specific) Enoyl-[acyl-carrier-protein] reductase (NADPH, B-specific)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.10 1.3.1.10] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4fs3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fs3 OCA], [https://pdbe.org/4fs3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fs3 RCSB], [https://www.ebi.ac.uk/pdbsum/4fs3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fs3 ProSAT]</span></td></tr>
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<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=4fs3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fs3 OCA], [http://pdbe.org/4fs3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4fs3 RCSB], [http://www.ebi.ac.uk/pdbsum/4fs3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4fs3 ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/FABI_STAAR FABI_STAAR]] Catalyzes the reduction of a carbon-carbon double bond in an enoyl moiety that is covalently linked to an acyl carrier protein (ACP). Involved in the elongation cycle of fatty acid which are used in the lipid metabolism (By similarity).
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[https://www.uniprot.org/uniprot/FABI_STAAR FABI_STAAR] Catalyzes the reduction of a carbon-carbon double bond in an enoyl moiety that is covalently linked to an acyl carrier protein (ACP). Involved in the elongation cycle of fatty acid which are used in the lipid metabolism (By similarity).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The mechanism of action of AFN-1252, a selective inhibitor of S. aureus enoyl-ACP reductase (FabI) which is involved in fatty acid biosynthesis, was confirmed using biochemistry, macromolecular synthesis, genetics and co-crystallization of a AFN-1252:FabI complex. AFN-1252 demonstrated low propensity for spontaneous resistance development; time-dependent reduction in viability of both MSSA and MRSA, achieving a &gt;/=2 log(10) reduction in S. aureus counts over 24 hours; and was extremely potent against clinical isolates of S. aureus (MIC(90) 0.015 mug/mL) and coagulase-negative staphylococci (MIC(90) 0.12 mug/mL) regardless of their drug-resistance, hospital- or community-associated origin or other clinical sub-group. AFN-1252 was orally available in mouse pharmacokinetic studies and a single oral dose of 1 mg/kg AFN-1252 was efficacious in a mouse model of septicemia providing 100% protection from an otherwise lethal peritoneal infection of S. aureus Smith. An ED(50) of 0.15 mg/kg indicated that AFN-1252 was 12- to 24 times more potent than linezolid in the model. These studies, demonstrating a selective mode of action, potent in vitro activity and in vivo efficacy support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections.
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AFN-1252 - Mode of action, in vitro activity and in vivo efficacy of a selective anti-staphylococcal FabI inhibitor.,Kaplan N, Albert M, Awrey D, Bardouniotis E, Berman J, Clarke T, Dorsey M, Hafkin B, Ramnauth J, Romanov V, Schmid MB, Thalakada R, Yethon J, Pauls HW Antimicrob Agents Chemother. 2012 Sep 4. PMID:22948878<ref>PMID:22948878</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4fs3" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Enoyl-Acyl-Carrier Protein Reductase|Enoyl-Acyl-Carrier Protein Reductase]]
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*[[Enoyl-Acyl-Carrier Protein Reductase 3D structures|Enoyl-Acyl-Carrier Protein Reductase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Staar]]
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[[Category: Large Structures]]
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[[Category: Albert, M]]
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[[Category: Staphylococcus aureus subsp. aureus MRSA252]]
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[[Category: Awrey, D E]]
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[[Category: Albert M]]
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[[Category: Bardouniotis, E]]
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[[Category: Awrey DE]]
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[[Category: Berman, J]]
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[[Category: Bardouniotis E]]
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[[Category: Clarke, T E]]
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[[Category: Berman J]]
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[[Category: Dorsey, M]]
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[[Category: Clarke TE]]
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[[Category: Kaplan, N]]
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[[Category: Dorsey M]]
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[[Category: Pauls, H W]]
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[[Category: Kaplan N]]
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[[Category: Ramnauth, J]]
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[[Category: Pauls HW]]
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[[Category: Romanov, V]]
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[[Category: Ramnauth J]]
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[[Category: Schmid, M B]]
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[[Category: Romanov V]]
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[[Category: Thalakada, R]]
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[[Category: Schmid MB]]
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[[Category: Yethon, J]]
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[[Category: Thalakada R]]
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[[Category: Nadph binding]]
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[[Category: Yethon J]]
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[[Category: Oxidoreductase]]
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[[Category: Rossmann fold]]
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[[Category: Short chain dehydrogenase]]
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Current revision

Crystal structure of Staphylococcus aureus enoyl-ACP reductase in complex with NADP and AFN-1252

PDB ID 4fs3

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