Journal:Acta Cryst F:S2053230X20011310

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

Gareth D. Fenn, Helen Waller-Evans, John R. Atack and Benjamin D. Bax ^[1]

Molecular Tour
Inositol monophosphatase (IMPase) is inhibited by lithium, 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 we present the crystallization and first structure of human IMPase covalently complexed with ebselen, a 1.47 Å crystal structure (PDB entry 6zk0). In the human-IMPase-complex 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 ~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.

Orthogonal views of IMPase dimer (and tetramer) showing ebselen on Cys141 and metal ions in the active sites based on the structure of PDB entry 6zk0:

• . Metal ions (Mn2+/Na+) at each active site are shown as spheres.
• .
• .

References

1. ↑ Fenn GD, Waller-Evans H, Atack JR, Bax BD. Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase. Acta Crystallogr F Struct Biol Commun. 2020 Oct 1;76(Pt 10):469-476. doi:, 10.1107/S2053230X20011310. Epub 2020 Sep 15. PMID:33006574 doi:http://dx.doi.org/10.1107/S2053230X20011310