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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
International Union of Crystallography
2020
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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. |
format | Online Article Text |
id | pubmed-7531247 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | International Union of Crystallography |
record_format | MEDLINE/PubMed |
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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