NMR Fragment Screening Hit Induces Plasticity of BRD7/9 Bromodomains. (27th June 2016)

• Record Type: Journal Article
• Authors: Wang, Na; Li, Fudong; Bao, Hongyu; Li, Jie; Wu, Jihui; Ruan, Ke
• Is Part Of: Chembiochem. Volume 17:Number 15(2016)
• Page Start: 1456
• Page End: 1463
• Publication Date: 2016-06-27
• Subjects: bromodomains -- conformational plasticity -- epigenetics -- NMR -- protein–protein interactions; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201600184
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: The complex biology associated with inhibition of bromodomain and extra‐terminal (BET) domains by chemical probes has attracted increasing attention, and there is a need to identify non‐BET bromodomain (BD) inhibitors. Several potent inhibitors of the BRD9 BD have recently been discovered, with anticancer and anti‐inflammation activity. However, its paralogue, BRD7 BD, remains unexploited. Here, we identified new chemotypes targeting BRD7 BD by using NMR fragment‐based screening. BRD7/9 BDs exhibit similar patterns of chemical‐shift perturbation upon the titration of hit compound1 . The crystal structure revealed that1 repels the Y222 group of BRD9 BD in a similar way to that for butyryllysine, but not acetyllysine and known inhibitors. Hit 1 induced less rearrangement of residue F161 of BRD9 BD than acetyllysine, butyryllysine, and crotonyllysine. Our study provides structural insight into a new generation of butyryllysine mimics for probing the function of BRD7/9 BD. Abstract : NMR fragment‐based screening identified a ligand to BRD7/9 bromodomains. The crystal structure of this compound in complex with BRD9 revealed that it induced a plasticity of BRD9 bromodomain similar to that effected by crotonyllysine.