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Mechanistic insights into peptide and ligand binding of the ATAD2-bromodomain via atomistic simulations disclosing a role of induced fit and conformational selection
KTH, School of Engineering Sciences (SCI), Mechanics, Structural Mechanics.ORCID iD: 0000-0002-3875-927X
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0002-3138-820X
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2018 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 20, no 36, p. 23222-23232Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2018. Vol. 20, no 36, p. 23222-23232
Keywords [en]
AAA protein, ATAD2 protein, human, DNA binding protein, ligand, peptide, binding site, chemistry, conformation, human, molecular dynamics, ATPases Associated with Diverse Cellular Activities, Binding Sites, DNA-Binding Proteins, Humans, Ligands, Molecular Conformation, Molecular Dynamics Simulation, Peptides
National Category
Atom and Molecular Physics and Optics
Identifiers
URN: urn:nbn:se:kth:diva-236425DOI: 10.1039/c8cp03860kISI: 000447370600005Scopus ID: 2-s2.0-85053795262OAI: oai:DiVA.org:kth-236425DiVA, id: diva2:1258990
Note

QC 20181026

Available from: 2018-10-26 Created: 2018-10-26 Last updated: 2018-11-06Bibliographically approved

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Zhou, YangGuanglin, KuangTu, Yaoquan

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