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Insights into Conformational Dynamics and Allostery in DNMT1-H3Ub/USP7 Interactions

Authors :
Yu Zhu
Fei Ye
Ziyun Zhou
Wanlin Liu
Zhongjie Liang
Guang Hu
Source :
Molecules, Vol 26, Iss 17, p 5153 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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.

Details

Language :
English
ISSN :
14203049
Volume :
26
Issue :
17
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.0a3e203031de4da6b99552dba4b9c1ab
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules26175153