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Hitting a Moving Target: Simulation and Crystallography Study of ATAD2 Bromodomain Blockers.

ABSTRACT: Small molecule ligand binding to the ATAD2 bromodomain is investigated here through the synergistic combination of molecular dynamics and protein crystallography. A previously unexplored conformation of the binding pocket upon rearrangement of the gatekeeper residue Ile1074 has been found. Further, our investigations reveal how minor structural differences in the ligands result in binding with different plasticity of the ZA loop for this difficult-to-drug bromodomain.

SUBMITTER: Dolbois A

PROVIDER: S-EPMC7429973 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Hitting a Moving Target: Simulation and Crystallography Study of ATAD2 Bromodomain Blockers.

Dolbois Aymeric A Batiste Laurent L Wiedmer Lars L Dong Jing J Brütsch Manuela M Huang Danzhi D Deerain Nicholas M NM Spiliotopoulos Dimitrios D Cheng-Sánchez Iván I Laul Eleen E Nevado Cristina C Śledź Paweł P Caflisch Amedeo A

ACS medicinal chemistry letters 20200630 8

Small molecule ligand binding to the ATAD2 bromodomain is investigated here through the synergistic combination of molecular dynamics and protein crystallography. A previously unexplored conformation of the binding pocket upon rearrangement of the gatekeeper residue Ile1074 has been found. Further, our investigations reveal how minor structural differences in the ligands result in binding with different plasticity of the ZA loop for this difficult-to-drug bromodomain. ...[more]

PMID: 32832026

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