4BO6
Crystal structure of 3-oxoacyl-(acyl-carrier-protein) reductase (FabG) from Pseudomonas aeruginosa in complex with 2,3-dihydroindol-1-yl-(2- thiophen-3-yl-1,3-thiazol-4-yl)methanone at 2.8A resolution
Summary for 4BO6
| Entry DOI | 10.2210/pdb4bo6/pdb |
| Related | 4BNT 4BNU 4BNV 4BNW 4BNX 4BNY 4BNZ 4BO0 4BO1 4BO2 4BO3 4BO4 4BO5 4BO7 4BO8 4BO9 |
| Descriptor | 3-OXOACYL-[ACYL-CARRIER-PROTEIN] REDUCTASE FABG, 2,3-dihydroindol-1-yl-(2-thiophen-3-yl-1,3-thiazol-4-yl)methanone (3 entities in total) |
| Functional Keywords | oxidoreductase, rossmann fold, fatty acid biosynthesis |
| Biological source | PSEUDOMONAS AERUGINOSA |
| Total number of polymer chains | 4 |
| Total formula weight | 113296.66 |
| Authors | Cukier, C.D.,Schnell, R.,Lindqvist, Y.,Schneider, G. (deposition date: 2013-05-18, release date: 2013-09-18, Last modification date: 2023-12-20) |
| Primary citation | Cukier, C.D.,Hope, A.,Elamin, A.,Moynie, L.,Schnell, R.,Schach, S.,Kneuper, H.,Singh, M.,Naismith, J.,Lindqvist, Y.,Gray, D.,Schneider, G. Discovery of an Allosteric Inhibitor Binding Site in 3-Oxo-Acyl-Acp Reductase from Pseudomonas Aeruginosa Acs Chem.Biol., 8:2518-, 2013 Cited by PubMed Abstract: 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 16 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. PubMed: 24015914DOI: 10.1021/CB4005063 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
Download full validation report
