Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase. Issue 10 (2nd October 2020)

• Record Type: Journal Article
• Authors: Fenn, Gareth D.; Waller-Evans, Helen; Atack, John R.; Bax, Benjamin D.
• Is Part Of: Acta crystallographica. Volume 76:Issue 10(2020:Oct.)
• Page Start: 469
• Page End: 476
• Publication Date: 2020-10-02
• Subjects: inositol monophosphatase -- IMPase -- ebselen -- bipolar disorder -- tetramer; Crystallography -- Periodicals; Crystals -- Periodicals; 548
• DOI: 10.1107/S2053230X20011310
• Languages: English
• ISSNs: 2053-230X

Abstract

Abstract : 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. Abstract : 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.