3QT6: Crystal Structure Of Staphylococcus Epidermidis Mevalonate Diphosphate Decarboxylase Complexed With Inhibitor Dpgp

Citation:
Abstract
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.
PDB ID: 3QT6Download
MMDB ID: 90482
PDB Deposition Date: 2011/2/22
Updated in MMDB: 2011/11
Experimental Method:
x-ray diffraction
Resolution: 2.05  Å
Source Organism:
Similar Structures:
Biological Unit for 3QT6: dimeric; determined by author and by software (PISA)
Molecular Components in 3QT6
Label Count Molecule
Proteins (2 molecules)
2
Mevalonate Diphosphate Decarboxylase
Molecule annotation
Chemicals (2 molecules)
1
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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