4bo8: Difference between revisions
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== | ==Crystal structure of 3-oxoacyl-(acyl-carrier-protein) reductase (FabG) from Pseudomonas aeruginosa in complex with 1-(2-amino-4- phenylimidazol-1-yl)-3-(2-fluorophenyl)urea at 2.7A resolution== | ||
[[http://www.uniprot.org/uniprot/FABG_PSEAE FABG_PSEAE | <StructureSection load='4bo8' size='340' side='right'caption='[[4bo8]], [[Resolution|resolution]] 2.70Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4bo8]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PAO1 Pseudomonas aeruginosa PAO1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BO8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BO8 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]] 2.7Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=34X:1-(2-AMINO-4-PHENYLIMIDAZOL-1-YL)-3-(2-FLUOROPHENYL)UREA'>34X</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4bo8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bo8 OCA], [https://pdbe.org/4bo8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bo8 RCSB], [https://www.ebi.ac.uk/pdbsum/4bo8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bo8 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/FABG_PSEAE FABG_PSEAE] Catalyzes the NADPH-dependent reduction of beta-ketoacyl-ACP substrates to beta-hydroxyacyl-ACP products, the first reductive step in the elongation cycle of fatty acid biosynthesis (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
3-oxo-acyl-acyl carrier protein (ACP) reductase (FabG) plays a key role in the bacterial fatty acid synthesis II system in pathogenic microorganisms, which has been recognized as a potential drug target. FabG catalyzes reduction of a 3-oxo-acyl-ACP intermediate during the elongation cycle of fatty acid biosynthesis. Here, we report gene deletion experiments that support the essentiality of this gene in P. aeruginosa and the identification of a number of small molecule FabG inhibitors with IC50 values in the nanomolar to low micromolar range and good physicochemical properties. Structural characterization of sixteen FabG-inhibitor complexes by X-ray crystallography revealed that the compounds bind at a novel allosteric site located at the FabG subunit-subunit interface. Inhibitor binding relies primarily on hydrophobic interactions, but specific hydrogen-bonds are also observed. Importantly, the binding cavity is formed upon complex formation and therefore would not be recognized by virtual screening approaches. The structure analysis further reveals that the inhibitors act by inducing conformational changes that propagate to the active site resulting in a displacement of the catalytic triad and the inability to bind NADPH. | |||
Discovery of an allosteric inhibitor binding site in 3-oxo-acyl-ACP reductase from Pseudomonas aeruginosa.,Cukier CD, Hope AG, Elamin AA, Moynie L, Schnell R, Schach S, Kneuper H, Singh M, Naismith JH, Lindqvist Y, Gray DW, Schneider G ACS Chem Biol. 2013 Sep 9. PMID:24015914<ref>PMID:24015914</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
< | </div> | ||
[[ | <div class="pdbe-citations 4bo8" style="background-color:#fffaf0;"></div> | ||
[[ | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Beta-hydroxyacyl-acyl carrier protein dehydratase 3D structures|Beta-hydroxyacyl-acyl carrier protein dehydratase 3D structures]] | ||
[[Category: | *[[Beta-ketoacyl carrier protein reductase 3D structures|Beta-ketoacyl carrier protein reductase 3D structures]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Pseudomonas aeruginosa PAO1]] | |||
[[Category: Cukier CD]] | |||
[[Category: Lindqvist Y]] | |||
[[Category: Schneider G]] | |||
[[Category: Schnell R]] | |||
Latest revision as of 14:55, 20 December 2023
Crystal structure of 3-oxoacyl-(acyl-carrier-protein) reductase (FabG) from Pseudomonas aeruginosa in complex with 1-(2-amino-4- phenylimidazol-1-yl)-3-(2-fluorophenyl)urea at 2.7A resolutionCrystal structure of 3-oxoacyl-(acyl-carrier-protein) reductase (FabG) from Pseudomonas aeruginosa in complex with 1-(2-amino-4- phenylimidazol-1-yl)-3-(2-fluorophenyl)urea at 2.7A resolution
Structural highlights
FunctionFABG_PSEAE Catalyzes the NADPH-dependent reduction of beta-ketoacyl-ACP substrates to beta-hydroxyacyl-ACP products, the first reductive step in the elongation cycle of fatty acid biosynthesis (By similarity). Publication Abstract from PubMed3-oxo-acyl-acyl carrier protein (ACP) reductase (FabG) plays a key role in the bacterial fatty acid synthesis II system in pathogenic microorganisms, which has been recognized as a potential drug target. FabG catalyzes reduction of a 3-oxo-acyl-ACP intermediate during the elongation cycle of fatty acid biosynthesis. Here, we report gene deletion experiments that support the essentiality of this gene in P. aeruginosa and the identification of a number of small molecule FabG inhibitors with IC50 values in the nanomolar to low micromolar range and good physicochemical properties. Structural characterization of sixteen FabG-inhibitor complexes by X-ray crystallography revealed that the compounds bind at a novel allosteric site located at the FabG subunit-subunit interface. Inhibitor binding relies primarily on hydrophobic interactions, but specific hydrogen-bonds are also observed. Importantly, the binding cavity is formed upon complex formation and therefore would not be recognized by virtual screening approaches. The structure analysis further reveals that the inhibitors act by inducing conformational changes that propagate to the active site resulting in a displacement of the catalytic triad and the inability to bind NADPH. Discovery of an allosteric inhibitor binding site in 3-oxo-acyl-ACP reductase from Pseudomonas aeruginosa.,Cukier CD, Hope AG, Elamin AA, Moynie L, Schnell R, Schach S, Kneuper H, Singh M, Naismith JH, Lindqvist Y, Gray DW, Schneider G ACS Chem Biol. 2013 Sep 9. PMID:24015914[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also
References
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