4RKS

Crystal Structure of Mevalonate-3-Kinase from Thermoplasma acidophilum (Mevalonate Bound)

Summary for 4RKS

• Entry DOI: 10.2210/pdb4rks/pdb
• Related: 4RKP 4RKZ
• Descriptor: Putative uncharacterized protein Ta1305, (R)-MEVALONATE, SULFATE ION, ... (6 entities in total)
• Functional Keywords: mevalonate, mevalonate-3-kinase, mevalonate pyrophosphate decarboxylase, mevalonate diphosphate decarboxylase, mevalonic acid, mevalonate kinase, transferase
• Biological source: Thermoplasma acidophilum
• Total number of polymer chains: 2
• Total formula weight: 75386.60

Authors

Vinokur, J.M.,Cascio, D.,Sawaya, M.R.,Bowie, J.U. (deposition date: 2014-10-13, release date: 2014-12-10, Last modification date: 2024-11-20)

Primary citation

Vinokur, J.M.,Korman, T.P.,Sawaya, M.R.,Collazo, M.,Cascio, D.,Bowie, J.U.
Structural analysis of mevalonate-3-kinase provides insight into the mechanisms of isoprenoid pathway decarboxylases.
Protein Sci., 24:212-220, 2015

PubMed Abstract: In animals, cholesterol is made from 5-carbon building blocks produced by the mevalonate pathway. Drugs that inhibit the mevalonate pathway such as atorvastatin (lipitor) have led to successful treatments for high cholesterol in humans. Another potential target for the inhibition of cholesterol synthesis is mevalonate diphosphate decarboxylase (MDD), which catalyzes the phosphorylation of (R)-mevalonate diphosphate, followed by decarboxylation to yield isopentenyl pyrophosphate. We recently discovered an MDD homolog, mevalonate-3-kinase (M3K) from Thermoplasma acidophilum, which catalyzes the identical phosphorylation of (R)-mevalonate, but without concomitant decarboxylation. Thus, M3K catalyzes half the reaction of the decarboxylase, allowing us to separate features of the active site that are required for decarboxylation from features required for phosphorylation. Here we determine the crystal structure of M3K in the apo form, and with bound substrates, and compare it to MDD structures. Structural and mutagenic analysis reveals modifications that allow M3K to bind mevalonate rather than mevalonate diphosphate. Comparison to homologous MDD structures show that both enzymes employ analogous Arg or Lys residues to catalyze phosphate transfer. However, an invariant active site Asp/Lys pair of MDD previously thought to play a role in phosphorylation is missing in M3K with no functional replacement. Thus, we suggest that the invariant Asp/Lys pair in MDD may be critical for decarboxylation rather than phosphorylation.

PubMed: 25422158
DOI: 10.1002/pro.2607

Experimental method

X-RAY DIFFRACTION (2 Å)