1KVK

The Structure of Binary complex between a Mammalian Mevalonate Kinase and ATP: Insights into the Reaction Mechanism and Human Inherited Disease

1KVK の概要

• エントリーDOI: 10.2210/pdb1kvk/pdb
• 分子名称: mevalonate kinase, MAGNESIUM ION, ADENOSINE-5'-TRIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: rmk, atp, ghmp, transferase
• 由来する生物種: Rattus norvegicus (Norway rat)
• 細胞内の位置: Cytoplasm: P17256
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42564.12

構造登録者

Fu, Z.,Wang, M.,Potter, D.,Mizioko, H.M.,Kim, J.J. (登録日: 2002-01-26, 公開日: 2002-03-27, 最終更新日: 2024-02-14)

主引用文献

Fu, Z.,Wang, M.,Potter, D.,Mizioko, H.M.,Kim, J.J.
The Structure of a Binary complex between a Mammalian Mevalonate Kinase and ATP: Insights into the Reaction Mechanism and Human Inherited Disease
J.Biol.Chem., 277:18134-18142, 2002

PubMed Abstract: Mevalonate kinase catalyzes the ATP-dependent phosphorylation of mevalonic acid to form mevalonate 5-phosphate, a key intermediate in the pathways of isoprenoids and sterols. Deficiency in mevalonate kinase activity has been linked to mevalonic aciduria and hyperimmunoglobulinemia D/periodic fever syndrome (HIDS). The crystal structure of rat mevalonate kinase in complex with MgATP has been determined at 2.4-A resolution. Each monomer of this dimeric protein is composed of two domains with its active site located at the domain interface. The enzyme-bound ATP adopts an anti conformation, in contrast to the syn conformation reported for Methanococcus jannaschii homoserine kinase. The Mg(2+) ion is coordinated to both beta- and gamma-phosphates of ATP and side chains of Glu(193) and Ser(146). Asp(204) is making a salt bridge with Lys(13), which in turn interacts with the gamma-phosphate. A model of mevalonic acid can be placed near the gamma-phosphoryl group of ATP; thus, the C5 hydroxyl is located within 4 A from Asp(204), Lys(13), and the gamma-phosphoryl of ATP. This arrangement of residues strongly suggests: 1) Asp(204) abstracts the proton from C5 hydroxyl of mevalonate; 2) the penta-coordinated gamma-phosphoryl group may be stabilized by Mg(2+), Lys(13), and Glu(193); and 3) Lys(13) is likely to influence the pK(a) of the C5 hydroxyl of the substrate. V377I and I268T are the most common mutations found in patients with HIDS. Val(377) is located over 18 A away from the active site and a conservative replacement with Ile is unlikely to yield an inactive or unstable protein. Ile-268 is located at the dimer interface, and its Thr substitution may disrupt dimer formation.

PubMed: 11877411
DOI: 10.1074/jbc.M200912200

実験手法

X-RAY DIFFRACTION (2.4 Å)