6HAZ

Crystal structure of the bromodomain of human SMARCA2 in complex with SMARCA-BD ligand

6HAZ の概要

• エントリーDOI: 10.2210/pdb6haz/pdb
• 分子名称: Probable global transcription activator SNF2L2, 2-(6-azanyl-5-piperazin-4-ium-1-yl-pyridazin-3-yl)phenol, ZINC ION, ... (4 entities in total)
• 機能のキーワード: bromodomain, gene regulation
• 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: 29436.55

構造登録者

Bader, G.,Steurer, S.,Weiss-Puxbaum, A.,Zoephel, A.,Roy, M.,Ciulli, A. (登録日: 2018-08-09, 公開日: 2019-06-12, 最終更新日: 2024-01-17)

主引用文献

Farnaby, W.,Koegl, M.,Roy, M.J.,Whitworth, C.,Diers, E.,Trainor, N.,Zollman, D.,Steurer, S.,Karolyi-Oezguer, J.,Riedmueller, C.,Gmaschitz, T.,Wachter, J.,Dank, C.,Galant, M.,Sharps, B.,Rumpel, K.,Traxler, E.,Gerstberger, T.,Schnitzer, R.,Petermann, O.,Greb, P.,Weinstabl, H.,Bader, G.,Zoephel, A.,Weiss-Puxbaum, A.,Ehrenhofer-Wolfer, K.,Wohrle, S.,Boehmelt, G.,Rinnenthal, J.,Arnhof, H.,Wiechens, N.,Wu, M.Y.,Owen-Hughes, T.,Ettmayer, P.,Pearson, M.,McConnell, D.B.,Ciulli, A.
BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.
Nat.Chem.Biol., 15:672-680, 2019

PubMed Abstract: Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.

PubMed: 31178587
DOI: 10.1038/s41589-019-0294-6

実験手法

X-RAY DIFFRACTION (1.31 Å)