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Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase

DOI: 10.1107/S2053230X20011310 DOI Help

Authors: Gareth D. Fenn (Cardiff University) , Helen Waller-evans (Cardiff University) , John R. Atack (Cardiff University) , Benjamin D. Bax (Cardiff University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acta Crystallographica Section F Structural Biology Communications , VOL 76

State: Published (Approved)
Published: October 2020
Diamond Proposal Number(s): 20147

Open Access Open Access

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.

Journal Keywords: inositol monophosphatase; IMPase; ebselen; bipolar disorder; tetramer

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)