2BJI

High Resolution Structure of myo-Inositol Monophosphatase, The Target of Lithium Therapy

2BJI の概要

• エントリーDOI: 10.2210/pdb2bji/pdb
• 分子名称: INOSITOL-1(OR 4)-MONOPHOSPHATASE, MAGNESIUM ION (3 entities in total)
• 機能のキーワード: hydrolase, aspartic proteinase mechanism, aspartyl protease, succinimide, zymogen
• 由来する生物種: BOS TAURUS (BOVINE)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 60318.96

構造登録者

Gill, R.,Mohammed, F.,Badyal, R.,Coates, L.,Erskine, P.,Thompson, D.,Cooper, J.,Gore, M.,Wood, S. (登録日: 2005-02-03, 公開日: 2005-02-11, 最終更新日: 2023-12-13)

主引用文献

Gill, R.,Mohammed, F.,Badyal, R.,Coates, L.,Erskine, P.,Thompson, D.,Cooper, J.,Gore, M.,Wood, S.
High-resolution structure of myo-inositol monophosphatase, the putative target of lithium therapy.
Acta Crystallogr. D Biol. Crystallogr., 61:545-555, 2005

PubMed Abstract: Inositol monophosphatase is a key enzyme of the phosphatidylinositol signalling pathway and the putative target of the mood-stabilizing drug lithium. The crystal structure of bovine inositol monophosphatase has been determined at 1.4 A resolution in complex with the physiological magnesium ion ligands. Three magnesium ions are octahedrally coordinated at the active site of each of the two subunits of the inositol monophosphatase dimer and a detailed three-metal mechanism is proposed. Ligands to the three metals include the side chains of Glu70, Asp90, Asp93 and Asp220, the backbone carbonyl group of Ile92 and several solvent molecules, including the proposed nucleophilic water molecule (W1) ligated by both Mg-1 and Mg-3. Modelling of the phosphate moiety of inositol monophosphate to superpose the axial phosphate O atoms onto three active-site water molecules orientates the phosphoester bond for in-line attack by the nucleophilic water which is activated by Thr95. Modelling of the pentacoordinate transition state suggests that the 6-OH group of the inositol moiety stabilizes the developing negative charge by hydrogen bonding to a phosphate O atom. Modelling of the post-reaction complex suggests a role for a second water molecule (W2) ligated by Mg-2 and Asp220 in protonating the departing inositolate. This second water molecule is absent in related structures in which lithium is bound at site 2, providing a rationale for enzyme inhibition by this simple monovalent cation. The higher resolution structural information on the active site of inositol monophosphatase will facilitate the design of substrate-based inhibitors and aid in the development of better therapeutic agents for bipolar disorder (manic depression).

PubMed: 15858264
DOI: 10.1107/S0907444905004038

実験手法

X-RAY DIFFRACTION (1.24 Å)