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Hitting a moving target: simulation and crystallography study of ATAD2 bromodomain blockers

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Authors:
A. Dolbois; L. Batiste; L. Wiedmer; J. Dong; M. Brütsch; D. Huang; N. Deerain; D. Spiliotopoulos; I. Cheng-Sánchez; E. Laul; C. Nevado; P. Śledź; A. Caflisch

Journal: ACS Med. Chem. Lett.
Year: 2020
Volume: 11
Issue: 8
Pages: 1573-1580
DOI: 10.1021/acsmedchemlett.0c00080
Type of Publication: Journal Article

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.