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

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...

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Autores principales: Fenn, Gareth D., Waller-Evans, Helen, Atack, John R., Bax, Benjamin D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Union of Crystallography 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531247/
https://www.ncbi.nlm.nih.gov/pubmed/33006574
http://dx.doi.org/10.1107/S2053230X20011310
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author Fenn, Gareth D.
Waller-Evans, Helen
Atack, John R.
Bax, Benjamin D.
author_facet Fenn, Gareth D.
Waller-Evans, Helen
Atack, John R.
Bax, Benjamin D.
author_sort Fenn, Gareth D.
collection PubMed
description 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.
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spelling pubmed-75312472020-10-27 Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase Fenn, Gareth D. Waller-Evans, Helen Atack, John R. Bax, Benjamin D. Acta Crystallogr F Struct Biol Commun Research Communications 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. International Union of Crystallography 2020-09-15 /pmc/articles/PMC7531247/ /pubmed/33006574 http://dx.doi.org/10.1107/S2053230X20011310 Text en © Fenn et al. 2020 http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.http://creativecommons.org/licenses/by/4.0/
spellingShingle Research Communications
Fenn, Gareth D.
Waller-Evans, Helen
Atack, John R.
Bax, Benjamin D.
Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase
title Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase
title_full Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase
title_fullStr Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase
title_full_unstemmed Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase
title_short Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase
title_sort crystallization and structure of ebselen bound to cys141 of human inositol monophosphatase
topic Research Communications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531247/
https://www.ncbi.nlm.nih.gov/pubmed/33006574
http://dx.doi.org/10.1107/S2053230X20011310
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