3am3

A372M mutant of Enoyl-ACP Reductase from Plasmodium falciparum (PfENR) in complex with triclosan

spinqualitylabelsall models 3am3, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3am3 is a 2 chain structure with sequence from Plafa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NAD, TCL Related: 1uh5, 1v35, 3lt0, 2aqh, 2aqk, 1cwu, 3am4, 3am5 Gene: FabI (PLAFA) Activity: [acyl-carrier-protein_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number 1.3.1.9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Enoyl acyl carrier protein reductase (ENR), which catalyzes the final and rate limiting step of fatty acid elongation, has been validated as a potential drug target. Triclosan is known to be an effective inhibitor for this enzyme. We mutated the substrate binding site residue Ala372 of the ENR of Plasmodium falciparum (PfENR) to Methionine and Valine which increased the affinity of the enzyme towards triclosan to almost double, close to that of Escherichia coli ENR (EcENR) which has a Methionine at the structurally similar position of Ala372 of PfENR. Kinetic studies of the mutants of PfENR and the crystal structure analysis of the A372M mutant revealed that a more hydrophobic environment enhances the affinity of the enzyme for the inhibitor. A triclosan derivative showed a threefold increase in the affinity towards the mutants compared to the wild type, due to additional interactions with the A372M mutant as revealed by the crystal structure. The enzyme has a conserved salt bridge which stabilizes the substrate binding loop and appears to be important for the active conformation of the enzyme. We generated a second set of mutants to check this hypothesis. These mutants showed loss of function, except in one case, where the crystal structure showed that the substrate binding loop is stabilized by a water bridge network. Effect of substrate binding loop mutations on the structure, kinetics, and inhibition of enoyl acyl carrier protein reductase from plasmodium falciparum.,Maity K, Banerjee T, Prabakaran N, Surolia N, Surolia A, Suguna K IUBMB Life. 2011 Jan;63(1):30-41. doi: 10.1002/iub.412. Epub 2011 Jan 13. PMID:21280175 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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