Hitting a Moving Target: Simulation and Crystallography Study of ATAD2 Bromodomain Blockers
A. Dolbois, Laurent Batiste, L. Wiedmer, Jing Dong, Manuela M. Brütsch, Danzhi Huang, Nicholas Deerain, Dimitrios Spiliotopoulos, Iván Cheng‐Sánchez, Eleen Laul, Cristina Nevado, P. Sledz, Amedeo Caflisch
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.
Topics & Concepts
BromodomainMolecular dynamicsChemistrySmall moleculeLigand (biochemistry)Binding pocketCrystallographyStereochemistryBiophysicsBinding siteBiochemistryComputational chemistryBiologyReceptorDNAHistoneProtein Degradation and InhibitorsMultiple Myeloma Research and TreatmentsAdvanced biosensing and bioanalysis techniques