4RKS

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

4RKS の概要

• エントリーDOI: 10.2210/pdb4rks/pdb
• 関連するPDBエントリー: 4RKP 4RKZ
• 分子名称: Putative uncharacterized protein Ta1305, (R)-MEVALONATE, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: mevalonate, mevalonate-3-kinase, mevalonate pyrophosphate decarboxylase, mevalonate diphosphate decarboxylase, mevalonic acid, mevalonate kinase, transferase
• 由来する生物種: Thermoplasma acidophilum
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75386.60

構造登録者

Vinokur, J.M.,Cascio, D.,Sawaya, M.R.,Bowie, J.U. (登録日: 2014-10-13, 公開日: 2014-12-10, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2 Å)