Jump to main content
Jump to site search

Issue 36, 2018
Previous Article Next Article

Mechanistic insights into peptide and ligand binding of the ATAD2-bromodomain via atomistic simulations disclosing a role of induced fit and conformational selection

Author affiliations

Abstract

ATAD2 has emerged as a promising bromodomain (BRD)-containing therapeutic drug target in multiple human cancers. However, recent druggability assessment studies predicted ATAD2's BRD as a target ‘difficult to drug’ because its binding pocket possesses structural features that are unfeasible for ligand binding. Here, by using all-atom molecular dynamics simulations and an advanced metadynamics method, we demonstrate a dynamic view of the binding pocket features which can hardly be obtained from the “static” crystal data. The most important features disclosed from our simulation data, include: (1) a distinct ‘open-to-closed’ conformational switch of the ZA loop region in the context of peptide or ligand binding, akin to the induced fit mechanism of molecular recognition, (2) a dynamic equilibrium of the BC loop “in” and “out” conformations, highlighting a role in the conformational selection mechanism for ligand binding, and (3) a new binding region identified distal to the histone-binding pocket that might have implications in bromodomain biology and in inhibitor development. Moreover, based on our simulation results, we propose a model for an “auto-regulatory” mechanism of ATAD2's BRD for histone binding. Overall, the results of this study will not only have implications in bromodomain biology but also provide a theoretical basis for the discovery of new ATAD2's BRD inhibitors.

Graphical abstract: Mechanistic insights into peptide and ligand binding of the ATAD2-bromodomain via atomistic simulations disclosing a role of induced fit and conformational selection

Back to tab navigation

Supplementary files

Publication details

The article was received on 18 Jun 2018, accepted on 08 Aug 2018 and first published on 08 Aug 2018


Article type: Paper
DOI: 10.1039/C8CP03860K
Citation: Phys. Chem. Chem. Phys., 2018,20, 23222-23232
  •   Request permissions

    Mechanistic insights into peptide and ligand binding of the ATAD2-bromodomain via atomistic simulations disclosing a role of induced fit and conformational selection

    Y. Zhou, M. Hussain, G. Kuang, J. Zhang and Y. Tu, Phys. Chem. Chem. Phys., 2018, 20, 23222
    DOI: 10.1039/C8CP03860K

Search articles by author

Spotlight

Advertisements