title: NMR Fragment Screening Hit Induces Plasticity of BRD7/9 Bromodomains.
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 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.
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Fudong
authors.initials: F
authors.lastname: Li
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Bao
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Jihui
authors.initials: J
authors.lastname: Wu
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, China. kruan@ustc.edu.cn.
authors.forename: Ke
authors.initials: K
authors.lastname: Ruan
mesh_terms: D002087:Butyrates; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D008239:Lysine / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D018716:Molecular Mimicry; D015335:Molecular Probes; D010446:Peptide Fragments; D000072417:Protein Domains; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000092468:Bromodomain Containing Proteins
chemical_list: D002087:Butyrates; D002868:Chromosomal Proteins, Non-Histone; D008239:Lysine; D015335:Molecular Probes; D010446:Peptide Fragments; D014157:Transcription Factors; C485694:BRD7 protein, human; D000092468:Bromodomain Containing Proteins; C587454:BRD9 protein, human
keywords: NMR; bromodomains; conformational plasticity; epigenetics; protein-protein interactions