STRUCTURE OF INOSITOL MONOPHOSPHATASE, THE PUTATIVE TARGET OF LITHIUM-THERAPY
STRUCTURE OF INOSITOL MONOPHOSPHATASE, THE PUTATIVE TARGET OF LITHIUM-THERAPY
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DOI：
10.1073/pnas.89.21.10031
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发表时间：
1992-11-01
影响因子：
11.1
通讯作者：
ATACK, JR
中科院分区：
文献类型：
--
作者：
BONE, R;SPRINGER, JP;ATACK, JR
肌醇单磷酸酶（EC 3.1.3.25）是锂治疗躁狂抑郁症的假定分子作用位点，通过催化肌醇单磷酸的水解在磷脂酰肌醇信号通路中起关键作用。为了提供一个结构基础，从设计更好的治疗药物，躁狂抑郁症，人肌醇单磷酸酶的结构已被确定为2.1埃分辨率通过使用X射线晶体学。这种酶以相同亚基的二聚体形式存在，每个亚基折叠成三对α螺旋和两个β折叠的五层三明治。硫酸盐和抑制性镧系阳离子（Gd 3+）结合在每个亚基上的相同位点，并建立活性位点的位置。每个站点位于一个大型亲水洞穴中，该洞穴位于两个中央螺旋的底部，其中几个二级结构段相交。几个不同基因的磷酸酶序列与磷酸酶结构的比较表明，这些基因的产物和磷酸酶形成一个具有保守的金属结合位点的结构家族。
Inositol monophosphatase (EC 3.1.3.25), the putative molecular site of action of lithium therapy for manic-depressive illness, plays a key role in the phosphatidylinositol signaling pathway by catalyzing the hydrolysis of inositol monophosphates. To provide a structural basis from which to design better therapeutic agents for manic-depressive illness, the structure of human inositol monophosphatase has been determined to 2.1-angstrom resolution by using x-ray crystallography. The enzyme exists as a dimer of identical subunits, each folded into a five-layered sandwich of three pairs of alpha-helices and two beta-sheets. Sulfate and an inhibitory lanthanide cation (Gd3+) are bound at identical sites on each subunit and establish the positions of the active sites. Each site is located in a large hydrophilic cavern that is at the base of the two central helices where several segments of secondary structure intersect. Comparison of the phosphatase aligned sequences of several diverse genes with the phosphatase structure suggests that the products of these genes and the phosphatase form a structural family with a conserved metal binding site.