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Insights into Conformational Dynamics and Allostery in DNMT1-H3Ub/USP7 Interactions
DNA methyltransferases (DNMTs) including DNMT1 are a conserved family of cytosine methylases that play crucial roles in epigenetic regulation. The versatile functions of DNMT1 rely on allosteric networks between its different interacting partners, emerging as novel therapeutic targets. In this work,...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434485/ https://www.ncbi.nlm.nih.gov/pubmed/34500587 http://dx.doi.org/10.3390/molecules26175153 |
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author | Zhu, Yu Ye, Fei Zhou, Ziyun Liu, Wanlin Liang, Zhongjie Hu, Guang |
author_facet | Zhu, Yu Ye, Fei Zhou, Ziyun Liu, Wanlin Liang, Zhongjie Hu, Guang |
author_sort | Zhu, Yu |
collection | PubMed |
description | DNA methyltransferases (DNMTs) including DNMT1 are a conserved family of cytosine methylases that play crucial roles in epigenetic regulation. The versatile functions of DNMT1 rely on allosteric networks between its different interacting partners, emerging as novel therapeutic targets. In this work, based on the modeling structures of DNMT1-ubiquitylated H3 (H3Ub)/ubiquitin specific peptidase 7 (USP7) complexes, we have used a combination of elastic network models, molecular dynamics simulations, structural residue perturbation, network modeling, and pocket pathway analysis to examine their molecular mechanisms of allosteric regulation. The comparative intrinsic and conformational dynamics analysis of three DNMT1 systems has highlighted the pivotal role of the RFTS domain as the dynamics hub in both intra- and inter-molecular interactions. The site perturbation and network modeling approaches have revealed the different and more complex allosteric interaction landscape in both DNMT1 complexes, involving the events caused by mutational hotspots and post-translation modification sites through protein-protein interactions (PPIs). Furthermore, communication pathway analysis and pocket detection have provided new mechanistic insights into molecular mechanisms underlying quaternary structures of DNMT1 complexes, suggesting potential targeting pockets for PPI-based allosteric drug design. |
format | Online Article Text |
id | pubmed-8434485 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-84344852021-09-12 Insights into Conformational Dynamics and Allostery in DNMT1-H3Ub/USP7 Interactions Zhu, Yu Ye, Fei Zhou, Ziyun Liu, Wanlin Liang, Zhongjie Hu, Guang Molecules Article DNA methyltransferases (DNMTs) including DNMT1 are a conserved family of cytosine methylases that play crucial roles in epigenetic regulation. The versatile functions of DNMT1 rely on allosteric networks between its different interacting partners, emerging as novel therapeutic targets. In this work, based on the modeling structures of DNMT1-ubiquitylated H3 (H3Ub)/ubiquitin specific peptidase 7 (USP7) complexes, we have used a combination of elastic network models, molecular dynamics simulations, structural residue perturbation, network modeling, and pocket pathway analysis to examine their molecular mechanisms of allosteric regulation. The comparative intrinsic and conformational dynamics analysis of three DNMT1 systems has highlighted the pivotal role of the RFTS domain as the dynamics hub in both intra- and inter-molecular interactions. The site perturbation and network modeling approaches have revealed the different and more complex allosteric interaction landscape in both DNMT1 complexes, involving the events caused by mutational hotspots and post-translation modification sites through protein-protein interactions (PPIs). Furthermore, communication pathway analysis and pocket detection have provided new mechanistic insights into molecular mechanisms underlying quaternary structures of DNMT1 complexes, suggesting potential targeting pockets for PPI-based allosteric drug design. MDPI 2021-08-25 /pmc/articles/PMC8434485/ /pubmed/34500587 http://dx.doi.org/10.3390/molecules26175153 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zhu, Yu Ye, Fei Zhou, Ziyun Liu, Wanlin Liang, Zhongjie Hu, Guang Insights into Conformational Dynamics and Allostery in DNMT1-H3Ub/USP7 Interactions |
title | Insights into Conformational Dynamics and Allostery in DNMT1-H3Ub/USP7 Interactions |
title_full | Insights into Conformational Dynamics and Allostery in DNMT1-H3Ub/USP7 Interactions |
title_fullStr | Insights into Conformational Dynamics and Allostery in DNMT1-H3Ub/USP7 Interactions |
title_full_unstemmed | Insights into Conformational Dynamics and Allostery in DNMT1-H3Ub/USP7 Interactions |
title_short | Insights into Conformational Dynamics and Allostery in DNMT1-H3Ub/USP7 Interactions |
title_sort | insights into conformational dynamics and allostery in dnmt1-h3ub/usp7 interactions |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434485/ https://www.ncbi.nlm.nih.gov/pubmed/34500587 http://dx.doi.org/10.3390/molecules26175153 |
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