4DPW

Crystal structure of Staphylococcus epidermidis D283A mevalonate diphosphate decarboxylase complexed with mevalonate diphosphate and ATPgS

Summary for 4DPW

• Entry DOI: 10.2210/pdb4dpw/pdb
• Related: 3QT5 3QT6 3QT7 3QT8 4DPT 4DPU 4DPX 4DPY 4DU7 4DU8
• Descriptor: Mevalonate diphosphate decarboxylase, PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER, (3R)-3-HYDROXY-5-{[(R)-HYDROXY(PHOSPHONOOXY)PHOSPHORYL]OXY}-3-METHYLPENTANOIC ACID, ... (6 entities in total)
• Functional Keywords: ghmp kinase family, lyase
• Biological source: Staphylococcus epidermidis
• Total number of polymer chains: 8
• Total formula weight: 301538.20

Authors

Barta, M.L.,McWhorter, W.J.,Geisbrecht, B.V. (deposition date: 2012-02-14, release date: 2012-07-11, Last modification date: 2023-09-13)

Primary citation

Barta, M.L.,McWhorter, W.J.,Miziorko, H.M.,Geisbrecht, B.V.
Structural basis for nucleotide binding and reaction catalysis in mevalonate diphosphate decarboxylase.
Biochemistry, 51:5611-5621, 2012

PubMed Abstract: Mevalonate diphosphate decarboxylase (MDD) catalyzes the final step of the mevalonate pathway, the Mg(2+)-ATP dependent decarboxylation of mevalonate 5-diphosphate (MVAPP), producing isopentenyl diphosphate (IPP). Synthesis of IPP, an isoprenoid precursor molecule that is a critical intermediate in peptidoglycan and polyisoprenoid biosynthesis, is essential in Gram-positive bacteria (e.g., Staphylococcus, Streptococcus, and Enterococcus spp.), and thus the enzymes of the mevalonate pathway are ideal antimicrobial targets. MDD belongs to the GHMP superfamily of metabolite kinases that have been extensively studied for the past 50 years, yet the crystallization of GHMP kinase ternary complexes has proven to be difficult. To further our understanding of the catalytic mechanism of GHMP kinases with the purpose of developing broad spectrum antimicrobial agents that target the substrate and nucleotide binding sites, we report the crystal structures of wild-type and mutant (S192A and D283A) ternary complexes of Staphylococcus epidermidis MDD. Comparison of apo, MVAPP-bound, and ternary complex wild-type MDD provides structural information about the mode of substrate binding and the catalytic mechanism. Structural characterization of ternary complexes of catalytically deficient MDD S192A and D283A (k(cat) decreased 10(3)- and 10(5)-fold, respectively) provides insight into MDD function. The carboxylate side chain of invariant Asp(283) functions as a catalytic base and is essential for the proper orientation of the MVAPP C3-hydroxyl group within the active site funnel. Several MDD amino acids within the conserved phosphate binding loop ("P-loop") provide key interactions, stabilizing the nucleotide triphosphoryl moiety. The crystal structures presented here provide a useful foundation for structure-based drug design.

PubMed: 22734632
DOI: 10.1021/bi300591x

Experimental method

X-RAY DIFFRACTION (2.605 Å)