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

ACS Med Chem Lett. 2020 Jun 30;11(8):1573-1580. doi: 10.1021/acsmedchemlett.0c00080. eCollection 2020 Aug 13.


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.