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Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs
Glycogen synthase kinase-3β (GSK3β) controls many physiological pathways, and is implicated in many diseases including Alzheimer’s and several cancers. GSK3β-mediated phosphorylation of target residues in microtubule-associated protein tau (MAPTAU) contributes to MAPTAU hyperphosphorylation and subs...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591898/ https://www.ncbi.nlm.nih.gov/pubmed/33110096 http://dx.doi.org/10.1038/s41598-020-75020-w |
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author | Balasubramaniam, Meenakshisundaram Mainali, Nirjal Bowroju, Suresh Kuarm Atluri, Paavan Penthala, Narsimha Reddy Ayyadevera, Srinivas Crooks, Peter A. Shmookler Reis, Robert J. |
author_facet | Balasubramaniam, Meenakshisundaram Mainali, Nirjal Bowroju, Suresh Kuarm Atluri, Paavan Penthala, Narsimha Reddy Ayyadevera, Srinivas Crooks, Peter A. Shmookler Reis, Robert J. |
author_sort | Balasubramaniam, Meenakshisundaram |
collection | PubMed |
description | Glycogen synthase kinase-3β (GSK3β) controls many physiological pathways, and is implicated in many diseases including Alzheimer’s and several cancers. GSK3β-mediated phosphorylation of target residues in microtubule-associated protein tau (MAPTAU) contributes to MAPTAU hyperphosphorylation and subsequent formation of neurofibrillary tangles. Inhibitors of GSK3β protect against Alzheimer’s disease and are therapeutic for several cancers. A thiadiazolidinone drug, TDZD-8, is a non-ATP-competitive inhibitor targeting GSK3β with demonstrated efficacy against multiple diseases. However, no experimental data or models define the binding mode of TDZD-8 with GSK3β, which chiefly reflects our lack of an established inactive conformation for this protein. Here, we used metadynamic simulation to predict the three-dimensional structure of the inactive conformation of GSK3β. Our model predicts that phosphorylation of GSK3β Serine9 would hasten the DFG-flip to an inactive state. Molecular docking and simulation predict the TDZD-8 binding conformation of GSK3β to be inactive, and are consistent with biochemical evidence for the TDZD-8–interacting residues of GSK3β. We also identified the pharmacophore and assessed binding efficacy of second-generation TDZD analogs (TDZD-10 and Tideglusib) that bind GSK3β as non-ATP-competitive inhibitors. Based on these results, the predicted inactive conformation of GSK3β can facilitate the identification of novel GSK3β inhibitors of high potency and specificity. |
format | Online Article Text |
id | pubmed-7591898 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75918982020-10-28 Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs Balasubramaniam, Meenakshisundaram Mainali, Nirjal Bowroju, Suresh Kuarm Atluri, Paavan Penthala, Narsimha Reddy Ayyadevera, Srinivas Crooks, Peter A. Shmookler Reis, Robert J. Sci Rep Article Glycogen synthase kinase-3β (GSK3β) controls many physiological pathways, and is implicated in many diseases including Alzheimer’s and several cancers. GSK3β-mediated phosphorylation of target residues in microtubule-associated protein tau (MAPTAU) contributes to MAPTAU hyperphosphorylation and subsequent formation of neurofibrillary tangles. Inhibitors of GSK3β protect against Alzheimer’s disease and are therapeutic for several cancers. A thiadiazolidinone drug, TDZD-8, is a non-ATP-competitive inhibitor targeting GSK3β with demonstrated efficacy against multiple diseases. However, no experimental data or models define the binding mode of TDZD-8 with GSK3β, which chiefly reflects our lack of an established inactive conformation for this protein. Here, we used metadynamic simulation to predict the three-dimensional structure of the inactive conformation of GSK3β. Our model predicts that phosphorylation of GSK3β Serine9 would hasten the DFG-flip to an inactive state. Molecular docking and simulation predict the TDZD-8 binding conformation of GSK3β to be inactive, and are consistent with biochemical evidence for the TDZD-8–interacting residues of GSK3β. We also identified the pharmacophore and assessed binding efficacy of second-generation TDZD analogs (TDZD-10 and Tideglusib) that bind GSK3β as non-ATP-competitive inhibitors. Based on these results, the predicted inactive conformation of GSK3β can facilitate the identification of novel GSK3β inhibitors of high potency and specificity. Nature Publishing Group UK 2020-10-27 /pmc/articles/PMC7591898/ /pubmed/33110096 http://dx.doi.org/10.1038/s41598-020-75020-w Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2020 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Balasubramaniam, Meenakshisundaram Mainali, Nirjal Bowroju, Suresh Kuarm Atluri, Paavan Penthala, Narsimha Reddy Ayyadevera, Srinivas Crooks, Peter A. Shmookler Reis, Robert J. Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs |
title | Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs |
title_full | Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs |
title_fullStr | Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs |
title_full_unstemmed | Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs |
title_short | Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs |
title_sort | structural modeling of gsk3β implicates the inactive (dfg-out) conformation as the target bound by tdzd analogs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591898/ https://www.ncbi.nlm.nih.gov/pubmed/33110096 http://dx.doi.org/10.1038/s41598-020-75020-w |
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