6VO4

Crystal Structure Analysis of BFL1

6VO4 の概要

• エントリーDOI: 10.2210/pdb6vo4/pdb
• 分子名称: Bcl-2-related protein A1 (2 entities in total)
• 機能のキーワード: bfl-1/a1, bcl-2 family, apoptosis, disulfide tethering, small molecule, inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18596.06

構造登録者

Seo, H.-S.,Dhe-Paganon, S. (登録日: 2020-01-29, 公開日: 2020-06-03, 最終更新日: 2023-10-11)

主引用文献

Harvey, E.P.,Hauseman, Z.J.,Cohen, D.T.,Rettenmaier, T.J.,Lee, S.,Huhn, A.J.,Wales, T.E.,Seo, H.S.,Luccarelli, J.,Newman, C.E.,Guerra, R.M.,Bird, G.H.,Dhe-Paganon, S.,Engen, J.R.,Wells, J.A.,Walensky, L.D.
Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering.
Cell Chem Biol, 27:647-, 2020

PubMed Abstract: The BCL-2 family is composed of anti- and pro-apoptotic members that respectively protect or disrupt mitochondrial integrity. Anti-apoptotic overexpression can promote oncogenesis by trapping the BCL-2 homology 3 (BH3) "killer domains" of pro-apoptotic proteins in a surface groove, blocking apoptosis. Groove inhibitors, such as the relatively large BCL-2 drug venetoclax (868 Da), have emerged as cancer therapies. BFL-1 remains an undrugged oncogenic protein and can cause venetoclax resistance. Having identified a unique C55 residue in the BFL-1 groove, we performed a disulfide tethering screen to determine if C55 reactivity could enable smaller molecules to block BFL-1's BH3-binding functionality. We found that a disulfide-bearing N-acetyltryptophan analog (304 Da adduct) effectively targeted BFL-1 C55 and reversed BFL-1-mediated suppression of mitochondrial apoptosis. Structural analyses implicated the conserved leucine-binding pocket of BFL-1 as the interaction site, resulting in conformational remodeling. Thus, therapeutic targeting of BFL-1 may be achievable through the design of small, cysteine-reactive drugs.

PubMed: 32413285
DOI: 10.1016/j.chembiol.2020.04.004

実験手法

X-RAY DIFFRACTION (1.74 Å)