3qt7 | pdb_00003qt7

Crystal structure of Staphylococcus epidermidis mevalonate diphosphate decarboxylase complexed with inhibitor 6-FMVAPP

spinqualitylabelsall models 3qt7, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3qt7 is a 2 chain structure with sequence from "albococcus_epidermidis"_winslow_and_winslow_1908 "albococcus epidermidis" winslow and winslow 1908. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: FM0 Related: 3qt5, 3qt6, 3qt8 Gene: mvaD ("Albococcus epidermidis" Winslow and Winslow 1908) Activity: Diphosphomevalonate decarboxylase, with EC number 4.1.1.33 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The polyisoprenoid compound undecaprenyl phosphate is required for biosynthesis of cell wall peptidoglycans in gram-positive bacteria, including pathogenic Enterococcus, Streptococcus, and Staphylococcus spp. In these organisms, the mevalonate pathway is used to produce the precursor isoprenoid, isopentenyl 5-diphosphate. Mevalonate diphosphate decarboxylase (MDD) catalyzes formation of isopentenyl 5-diphosphate in an ATP-dependent irreversible reaction and is therefore an attractive target for inhibitor development that could lead to new antimicrobial agents. To facilitate exploration of this possibility, we report the crystal structure of Staphylococcus epidermidis MDD (1.85 A resolution) and, to the best of our knowledge, the first structures of liganded MDD. These structures include MDD bound to the mevalonate 5-diphosphate analogs diphosphoglycolyl proline (2.05 A resolution) and 6-fluoromevalonate diphosphate (FMVAPP; 2.2 A resolution). Comparison of these structures provides a physical basis for the significant differences in K(i) values observed for these inhibitors. Inspection of enzyme/inhibitor structures identified the side chain of invariant Ser(192) as making potential contributions to catalysis. Significantly, Ser --> Ala substitution of this side chain decreases k(cat) by approximately 10(3)-fold, even though binding interactions between FMVAPP and this mutant are similar to those observed with wild type MDD, as judged by the 2.1 A cocrystal structure of S192A with FMVAPP. Comparison of microbial MDD structures with those of mammalian counterparts reveals potential targets at the active site periphery that may be exploited to selectively target the microbial enzymes. These studies provide a structural basis for previous observations regarding the MDD mechanism and inform future work toward rational inhibitor design. Crystal structures of Staphylococcus epidermidis mevalonate diphosphate decarboxylase bound to inhibitory analogs reveal new insight into substrate binding and catalysis.,Barta ML, Skaff DA, McWhorter WJ, Herdendorf TJ, Miziorko HM, Geisbrecht BV J Biol Chem. 2011 Jul 8;286(27):23900-10. Epub 2011 May 11. PMID:21561869 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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