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

TitleHitting a moving target: simulation and crystallography study of ATAD2 bromodomain blockers
Publication TypeJournal Article
Year of Publication2020
AuthorsDolbois A., Batiste L., Wiedmer L., Dong J., Brütsch M., Huang D., Deerain N., Spiliotopoulos D., Cheng-Sánchez I., Laul E., Nevado C., Śledź P., Caflisch A.
JournalACS Medicinal Chemistry Letters
Volume11
Issue8
Pagination1573-1580
Date Published2020 Aug 13
Type of ArticleResearch Article
ISSN1948-5875
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.

DOI10.1021/acsmedchemlett.0c00080
pubindex

0257

Alternate JournalACS Med. Chem. Lett.
PubMed ID32832026
PubMed Central IDPMC7429973