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.
BT - ACS Medicinal Chemistry Letters C1 - 0257 DA - 2020 Aug 13 DO - 10.1021/acsmedchemlett.0c00080 IS - 8 J2 - ACS Med. Chem. Lett. LA - eng M3 - Research Article N2 -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.
PY - 2020 SP - 1573 EP - 1580 T2 - ACS Medicinal Chemistry Letters TI - Hitting a moving target: simulation and crystallography study of ATAD2 bromodomain blockers VL - 11 SN - 1948-5875 ER -