5w3k | pdb_00005w3k

Crystal structure of Staphylococcus aureus ketol-acid reductoisomerase in complex NADPH, Mg2+ and CPD

spinqualitylabelsall models 5w3k, resolution 1.59Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5w3k is a 2 chain structure with sequence from Staphylococcus aureus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.589Å Ligands: 9TY, MG, NDP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ILVC_STAA8 Involved in the biosynthesis of branched-chain amino acids (BCAA). Catalyzes an alkyl-migration followed by a ketol-acid reduction of (S)-2-acetolactate (S2AL) to yield (R)-2,3-dihydroxy-isovalerate. In the isomerase reaction, S2AL is rearranged via a Mg-dependent methyl migration to produce 3-hydroxy-3-methyl-2-ketobutyrate (HMKB). In the reductase reaction, this 2-ketoacid undergoes a metal-dependent reduction by NADPH to yield (R)-2,3-dihydroxy-isovalerate.[HAMAP-Rule:MF_00435] Publication Abstract from PubMed Ketol-acid reductoisomerase (KARI) is an NAD(P)H and Mg2+-dependent enzyme of the branched-chain amino acid (BCAA) biosynthesis pathway. Here we describe the first crystal structures of Staphylococcus aureus (Sa) KARI, these in complex with two transition state analogs, cyclopropane-1,1-dicarboxylate (CPD) and N-isopropyloxalyl hydroxamate (IpOHA). These compounds bind competitively and in multi-dentate manner to KARI with Ki values of 2.73 muM and 7.9 nM, respectively; however, IpOHA binds slowly to the enzyme. Interestingly, intact IpOHA is present in only ~25% of binding sites, while its deoxygenated form is present in the remaining sites. This deoxy form of IpOHA binds rapidly to Sa KARI, but with much weaker affinity (Ki = 21 muM). Thus, our data pinpoint the origin of the slow binding mechanism of IpOHA. Furthermore, we propose that CPD mimics the early stage of the catalytic reaction (preceding the reduction step), while IpOHA mimics the late stage (after the reduction took place). These structural insights will guide strategies to design potent and rapidly binding derivatives of these compound for the development of novel biocides. Crystal structures of Staphylococcus aureus ketol-acid reductoisomerase in complex with two transition state analogs that have biocidal activity.,Patel K, Teran D, Zheng S, Kandale A, Garcia M, Lv Y, Schembri MA, McGeary RP, Schenk G, Guddat LW Chemistry. 2017 Oct 4. doi: 10.1002/chem.201704481. PMID:28975665 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ketol-acid reductoisomerase 3D structures

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