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. 2020 Oct 1;76(Pt 10):469-476.
doi: 10.1107/S2053230X20011310. Epub 2020 Sep 15.

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

Gareth D Fenn  1 , Helen Waller-Evans  1 , John R Atack  1 , Benjamin D Bax  1
Affiliations

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

Gareth D Fenn et al. Acta Crystallogr F Struct Biol Commun. .

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.

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

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Figures

Figure 1
Figure 1
View of ebselen attached to Cys141 (PDB entry 6zk0). (a) Overview of two ebselen molecules attached to the A and A′ (symmetry-related) subunits around the crystallographic twofold axis. One subunit (A) has C atoms in orange and the second subunit (A′) has C atoms in slate blue (N atoms are blue, O atoms are red, Se atoms are orange and S atoms are yellow-orange). C atoms in one ebselen are yellow and those in the second ebselen are cyan. Hydrogen bonds near ebselen are indicated by dotted lines. (b) Chemical structures of ebselen and ring-opened ebselen on Cys141 (drawn with Marvin; https://www.chemaxon.com). (c) Final ebselen OMIT map (F o − F c; 3σ, green; 15σ, blue). Note that the peaks on the seleniums (blue mesh) are 20.5σ and 19.6σ in this ebselen OMIT map. (d) Original DIMPLE (Wojdyr et al., 2013 ▸) 2F o − F c map (1σ, light blue) and F o − F c difference map (3σ, orange). For subunit A the DIMPLE-refined structure with waters (small red spheres) refined into the density for the ebselen is shown. For the A′ subunit the ‘final’ coordinates (including ebselen) are shown.
Figure 2
Figure 2
Cysteine residues in IMPase with ebselen bound to Cys141 (PDB entry 6zk0). IMPase is shown as a Cα ribbon trace and the side chains of the seven cysteines are shown as sticks on the ‘red’ subunit. The second subunit in the dimer is shown in cyan. A semi-transparent surface is shown; note that where the S atoms of the cysteine residues are on the surface of the protein, the surface is yellow (Cys24 and Cys141). Cys184 also has some surface accessibility in the monomer, but is largely buried at the dimer interface, so no yellow is visible for Cys184 in this figure.
Figure 3
Figure 3
Orthogonal views of the IMPase dimer (and tetramer) showing ebselen on Cys141 and metal ions in the active sites based on the structure of PDB entry 6zk0. (a) The two subunits in the dimer are shown as green (subunit A) and cyan (subunit B) cartoons, with ebselen attached to Cys141A and Cys141B in space-filling representation. Metal ions (Mn2+/Na+) at each active site are shown as grey spheres. (b, c) Orthogonal views. (d, e, f) The same views as in (a, b, c) but also showing a second dimer related by a crystallographic twofold axis. Subunit A′ is in yellow and subunit B′ is in magenta. The view in (e) is along the crystallographic twofold that rotates the AB dimer (green/cyan) onto the A′B′ dimer (yellow/magenta). (g, h). Two views of the tetramer from underneath, showing that the three metal ions (grey/black spheres) at each active site are still accessible in the tetramer. In (h), a surface is shown for both dimers.
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