Crystallization and structure of ebselen bound to cysteine 141 of human inositol monophosphatase (IMPase)

Fenn, Gareth, Waller-Evans, Helen ORCID: https://orcid.org/0000-0003-4133-6064, Atack, John R. ORCID: https://orcid.org/0000-0002-3410-791X and Bax, Benjamin D. ORCID: https://orcid.org/0000-0003-1940-3785 2020. Crystallization and structure of ebselen bound to cysteine 141 of human inositol monophosphatase (IMPase). Acta Crystallographica Section F: Structural Biology Communications F76 (10) , pp. 469-476. 10.1107/S2053230X20011310

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	International Union of Crystallography
ISSN:	2053-230X
Date of First Compliant Deposit:	9 September 2020
Date of Acceptance:	18 August 2020
Last Modified:	06 Mar 2024 02:07
URI:	https://orca.cardiff.ac.uk/id/eprint/134752

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