Biological Crystallography High-resolution Structure of Myo-inositol Monophosphatase, the Putative Target of Lithium Therapy
Biological Crystallography High-resolution Structure of Myo-inositol Monophosphatase, the Putative Target of Lithium Therapy
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锂疗法的假定靶点肌醇单磷酸酶的生物晶体学高分辨率结构
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通讯作者：
S. Wood
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作者：
R. Gill;F. Mohammed;R. Badyal;L. Coates;P. Erskine;D. Thompson;J. Cooper;M. Gore;S. Wood
肌醇单磷酸酶是磷脂酰肌醇信号通路的关键酶，也是情绪稳定药物锂的假定靶点。牛肌醇单磷酸酶的晶体结构已被确定在1.4 A的分辨率与生理镁离子配体的复合物。三个镁离子的八面体协调的肌醇单磷酸酶二聚体的两个亚基中的每一个的活性位点，并提出了一个详细的三金属机制。三种金属的配体包括Glu 70、Asp 90、Asp 93和Asp 220的侧链，Ile 92的骨架羰基和几种溶剂分子，包括由Mg-1和Mg-3连接的亲核水分子（W1）。肌醇单磷酸的磷酸部分的建模叠加到三个活性位点的水分子上的轴向磷酸O原子定向的磷酸酯键的亲核水，这是由Thr 95激活的在线攻击。五配位过渡态的建模表明，肌醇部分的6-OH基团通过与磷酸O原子的氢键合来稳定发展中的负电荷。反应后复合物的建模表明，Mg-2和Asp 220连接的第二个水分子（W2）在质子化离去的肌醇酯中的作用。这第二个水分子是不存在的相关结构中，锂是结合在网站2，提供了一个基本原理，酶抑制这种简单的一价阳离子。肌醇单磷酸酶活性位点的高分辨率结构信息将有助于设计基于底物的抑制剂，并有助于开发更好的双相情感障碍（躁狂抑郁症）治疗药物。PDB参考：肌醇单磷酸酶，2bji，r2 bjisf。
Inositol monophosphatase is a key enzyme of the phospha-tidylinositol 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). PDB Reference: myo-inositol monophosphatase, 2bji, r2bjisf.