NMR Fragment Screening Hit Induces Plasticity of BRD7/9 Bromodomains

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 anti...

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Published in:Chembiochem : a European journal of chemical biology 2016-08, Vol.17 (15), p.1456-1463
Main Authors: Wang, Na, Li, Fudong, Bao, Hongyu, Li, Jie, Wu, Jihui, Ruan, Ke
Format: Article
Language:English
Subjects:
bromodomains
Butyrates
Chromosomal Proteins, Non-Histone - antagonists & inhibitors
Chromosomal Proteins, Non-Histone - chemistry
conformational plasticity
Crystal structure
Crystallography, X-Ray
epigenetics
Humans
Lysine - chemistry
Magnetic Resonance Spectroscopy - methods
Molecular Mimicry
Molecular Probes
NMR
Peptide Fragments
Protein Domains
protein-protein interactions
Transcription Factors - antagonists & inhibitors
Transcription Factors - chemistry
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Summary: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 compound 1. The crystal structure revealed that 1 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. 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.
ISSN:1439-4227
1439-7633
DOI:10.1002/cbic.201600184