6HM0

Crystal structure of human BRD9 bromodomain in complex with a PROTAC

6HM0 の概要

• エントリーDOI: 10.2210/pdb6hm0/pdb
• 分子名称: Bromodomain-containing protein 9, (2~{S},4~{S})-1-[(2~{S})-2-[2-[2-[2-[4-[[2,6-dimethoxy-4-(2-methyl-1-oxidanylidene-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]-~{N}-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide (3 entities in total)
• 機能のキーワード: protac, lysine-acetylated histone binding, chromatin regulator, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30405.84

構造登録者

Hughes, S.J.,Zoppi, V.,Ciulli, A. (登録日: 2018-09-11, 公開日: 2019-01-16, 最終更新日: 2024-01-24)

主引用文献

Zoppi, V.,Hughes, S.J.,Maniaci, C.,Testa, A.,Gmaschitz, T.,Wieshofer, C.,Koegl, M.,Riching, K.M.,Daniels, D.L.,Spallarossa, A.,Ciulli, A.
Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel-Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7.
J.Med.Chem., 62:699-726, 2019

PubMed Abstract: Developing PROTACs to redirect the ubiquitination activity of E3 ligases and potently degrade a target protein within cells can be a lengthy and unpredictable process, and it remains unclear whether any combination of E3 and target might be productive for degradation. We describe a probe-quality degrader for a ligase-target pair deemed unsuitable: the von Hippel-Lindau (VHL) and BRD9, a bromodomain-containing subunit of the SWI/SNF chromatin remodeling complex BAF. VHL-based degraders could be optimized from suboptimal compounds in two rounds by systematically varying conjugation patterns and linkers and monitoring cellular degradation activities, kinetic profiles, and ubiquitination, as well as ternary complex formation thermodynamics. The emerged structure-activity relationships guided the discovery of VZ185, a potent, fast, and selective degrader of BRD9 and of its close homolog BRD7. Our findings qualify a new chemical tool for BRD7/9 knockdown and provide a roadmap for PROTAC development against seemingly incompatible target-ligase combinations.

PubMed: 30540463
DOI: 10.1021/acs.jmedchem.8b01413

実験手法

X-RAY DIFFRACTION (2.4 Å)