4ag3: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Crystal structure of 3-ketoacyl-(acyl-carrier-protein) reductase (FabG) from Pseudomonas aeruginosa in complex with NADPH at 1.8A resolution== | |||
<StructureSection load='4ag3' size='340' side='right' caption='[[4ag3]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4ag3]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Pseae Pseae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AG3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4AG3 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4afn|4afn]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/3-oxoacyl-[acyl-carrier-protein]_reductase 3-oxoacyl-[acyl-carrier-protein] reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.100 1.1.1.100] </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=4ag3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ag3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ag3 RCSB], [http://www.ebi.ac.uk/pdbsum/4ag3 PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://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> | |||
== | ==See Also== | ||
*[[Beta-ketoacyl-ACP reductase|Beta-ketoacyl-ACP reductase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Pseae]] | [[Category: Pseae]] | ||
[[Category: Cukier, C D | [[Category: Cukier, C D]] | ||
[[Category: Lindqvist, Y | [[Category: Lindqvist, Y]] | ||
[[Category: Schneider, G | [[Category: Schneider, G]] | ||
[[Category: Schnell, R | [[Category: Schnell, R]] | ||
[[Category: Fatty acid biosynthesis]] | [[Category: Fatty acid biosynthesis]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
[[Category: Rossmann fold]] | [[Category: Rossmann fold]] | ||
Revision as of 11:17, 25 December 2014
Crystal structure of 3-ketoacyl-(acyl-carrier-protein) reductase (FabG) from Pseudomonas aeruginosa in complex with NADPH at 1.8A resolutionCrystal structure of 3-ketoacyl-(acyl-carrier-protein) reductase (FabG) from Pseudomonas aeruginosa in complex with NADPH at 1.8A resolution
Structural highlights
Function[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). 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 AlsoReferences
|
| ||||||||||||||||||||