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Insights into Conformational Dynamics and Allostery in DNMT1-H3Ub/USP7 Interactions
- Source :
- Molecules; Volume 26; Issue 17; Pages: 5153, Molecules, Molecules, Vol 26, Iss 5153, p 5153 (2021)
- Publication Year :
- 2021
- Publisher :
- Multidisciplinary Digital Publishing Institute, 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.
- Subjects :
- DNA (Cytosine-5-)-Methyltransferase 1
Methyltransferase
allosteric communication
drug design
Protein Conformation
Allosteric regulation
protein-protein interactions
Pharmaceutical Science
Computational biology
Molecular Dynamics Simulation
Article
Epigenesis, Genetic
Analytical Chemistry
Protein–protein interaction
Histones
Ubiquitin-Specific Peptidase 7
Molecular dynamics
chemistry.chemical_compound
QD241-441
Allosteric Regulation
Drug Discovery
Humans
Protein Interaction Domains and Motifs
Epigenetics
Physical and Theoretical Chemistry
DNA methylation
DNMT1
Organic Chemistry
chemistry
Chemistry (miscellaneous)
Molecular Medicine
DNA
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 14203049
- Database :
- OpenAIRE
- Journal :
- Molecules; Volume 26; Issue 17; Pages: 5153
- Accession number :
- edsair.doi.dedup.....71bf99a9cfcbe486c1111da21ff68a71
- Full Text :
- https://doi.org/10.3390/molecules26175153