Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase.
Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase.
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DOI：
10.1107/s2053230x20011310
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发表时间：
2020-10-01
期刊：
影响因子：
--
通讯作者：
Bax BD
中科院分区：
文献类型：
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作者：
Fenn GD;Waller-Evans H;Atack JR;Bax BD
本文报道了与抑制剂依布硒啉结合的人肌醇单磷酸酶的晶体结构。在该结构中，依布硒形成硒硫键Cys141和依布硒介导的两个二聚体之间的接触给出一个四聚体与近似222对称性。肌醇单磷酸酶（IMP酶）被锂抑制，锂是治疗双相情感障碍最有效的药物。几种疗法已经获得批准，或正在进行临床试验，旨在替代锂治疗双相情感障碍。一个候选的小分子是依布硒啉，一种含硒的抗氧化剂，它已被证明在小鼠模型和临床试验中都能产生类似锂的作用。在这里，结晶和第一个结构的人IMP酶与依布硒啉共价复合，1.47 μ m分辨率的晶体结构（PDB条目6zk0），提出。 在与人IMPase的复合物中，开环构象的依布硒啉共价连接到Cys141，Cys141是远离活性位点的残基。IMPase是一种二聚体酶，在晶体结构中，两个相邻的二聚体共享四个依布硒啉分子，形成具有约222对称性的四聚体。在该出版物中呈现的晶体结构中，四聚体中的活性位点仍然是可接近的，这表明依布硒啉可以作为变构抑制剂起作用，或者可以阻断伴侣蛋白的结合。
A 1.47 Å resolution crystal structure of human inositol monophosphatase bound to the inhibitor ebselen is presented. In the structure, ebselen forms a selenosulfide bond to Cys141 and ebselen-mediated contacts between two dimers give a tetramer with approximate 222 symmetry. Inositol monophosphatase (IMPase) is inhibited by lithium, which is the most efficacious treatment for bipolar disorder. Several therapies have been approved, or are going through clinical trials, aimed at the replacement of lithium in the treatment of bipolar disorder. One candidate small molecule is ebselen, a selenium-containing antioxidant, which has been demonstrated to produce lithium-like effects both in a murine model and in clinical trials. Here, the crystallization and the first structure of human IMPase covalently complexed with ebselen, a 1.47 Å resolution crystal structure (PDB entry 6zk0), are presented. In the complex with human IMPase, ebselen in a ring-opened conformation is covalently attached to Cys141, a residue located away from the active site. IMPase is a dimeric enzyme and in the crystal structure two adjacent dimers share four ebselen molecules, creating a tetramer with approximate 222 symmetry. In the crystal structure presented in this publication, the active site in the tetramer is still accessible, suggesting that ebselen may function as an allosteric inhibitor or may block the binding of partner proteins.