The role of ZA channel water-mediated interactions in the design of bromodomain-selective BET inhibitors.

ABSTRACT: The Bromodomain and Extra-Terminal domain (BET) family of proteins are involved in the regulation of gene transcription, and their dysregulation is implicated in several diseases including cancer. BET proteins contain two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine residues and appear to have distinct biological roles. We compared several published co-crystal structures and found five positions near the substrate binding pocket that vary between BET bromodomains. One position located in the ZA loop has unique properties. In BRD2-4, this residue is glutamine in BD1 and lysine in BD2; in BRDT, this residue is arginine in BD1 and asparagine in BD2. Using molecular modeling, we identified differences in the water-mediated network at this position between br

SUBMITTER: Bharatham N 

PROVIDER: S-EPMC6524770 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature