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Molecular dynamics simulation reveals the possible druggable hot-spots of USP7
The plasticity in Ubiquitin Specific Proteases (USP7) inducing conformational changes at important areas has highlighted an intricate mechanism, by which USP7 is regulated. Given the importance of USP7 in oncogenic pathways and immune-oncology, identification of USP7 inhibitors has attracted conside...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188144/ https://www.ncbi.nlm.nih.gov/pubmed/30344943 http://dx.doi.org/10.18632/oncotarget.26136 |
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author | Srivastava, Mitul Suri, Charu Singh, Mrityunjay Mathur, Rajani Asthana, Shailendra |
author_facet | Srivastava, Mitul Suri, Charu Singh, Mrityunjay Mathur, Rajani Asthana, Shailendra |
author_sort | Srivastava, Mitul |
collection | PubMed |
description | The plasticity in Ubiquitin Specific Proteases (USP7) inducing conformational changes at important areas has highlighted an intricate mechanism, by which USP7 is regulated. Given the importance of USP7 in oncogenic pathways and immune-oncology, identification of USP7 inhibitors has attracted considerable interest. Despite substantial efforts, the discovery of deubiquitinases (DUBs) inhibitors, knowledge of their binding site and understanding the possible mechanism of action has proven particularly challenging. We disclose the most likely binding site of P5091 (a potent USP7 inhibitor), which reveal a cryptic allosteric site through extensive computational studies in an inhibitor dependent and independent manner. Overall, these findings demonstrate the tractability and druggability of USP7. Through a series of molecular dynamics simulations and detailed quantitative analysis, a dynamically stable allosteric binding site near catalytic center of the inactive state of USP7 (site partially absent in active state), along with two newly identified sites have been revealed, which opens the avenue for rational structure-guided inhibitor designing in USP7 specific-manner. |
format | Online Article Text |
id | pubmed-6188144 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-61881442018-10-21 Molecular dynamics simulation reveals the possible druggable hot-spots of USP7 Srivastava, Mitul Suri, Charu Singh, Mrityunjay Mathur, Rajani Asthana, Shailendra Oncotarget Research Paper The plasticity in Ubiquitin Specific Proteases (USP7) inducing conformational changes at important areas has highlighted an intricate mechanism, by which USP7 is regulated. Given the importance of USP7 in oncogenic pathways and immune-oncology, identification of USP7 inhibitors has attracted considerable interest. Despite substantial efforts, the discovery of deubiquitinases (DUBs) inhibitors, knowledge of their binding site and understanding the possible mechanism of action has proven particularly challenging. We disclose the most likely binding site of P5091 (a potent USP7 inhibitor), which reveal a cryptic allosteric site through extensive computational studies in an inhibitor dependent and independent manner. Overall, these findings demonstrate the tractability and druggability of USP7. Through a series of molecular dynamics simulations and detailed quantitative analysis, a dynamically stable allosteric binding site near catalytic center of the inactive state of USP7 (site partially absent in active state), along with two newly identified sites have been revealed, which opens the avenue for rational structure-guided inhibitor designing in USP7 specific-manner. Impact Journals LLC 2018-09-28 /pmc/articles/PMC6188144/ /pubmed/30344943 http://dx.doi.org/10.18632/oncotarget.26136 Text en Copyright: © 2018 Srivastava et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Srivastava, Mitul Suri, Charu Singh, Mrityunjay Mathur, Rajani Asthana, Shailendra Molecular dynamics simulation reveals the possible druggable hot-spots of USP7 |
title | Molecular dynamics simulation reveals the possible druggable hot-spots of USP7 |
title_full | Molecular dynamics simulation reveals the possible druggable hot-spots of USP7 |
title_fullStr | Molecular dynamics simulation reveals the possible druggable hot-spots of USP7 |
title_full_unstemmed | Molecular dynamics simulation reveals the possible druggable hot-spots of USP7 |
title_short | Molecular dynamics simulation reveals the possible druggable hot-spots of USP7 |
title_sort | molecular dynamics simulation reveals the possible druggable hot-spots of usp7 |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188144/ https://www.ncbi.nlm.nih.gov/pubmed/30344943 http://dx.doi.org/10.18632/oncotarget.26136 |
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