5WHI

Crystal Structure of Bcl-2-related protein A1

5WHI の概要

• エントリーDOI: 10.2210/pdb5whi/pdb
• 分子名称: Bcl-2-related protein A1, CACODYLIC ACID (3 entities in total)
• 機能のキーワード: apoptosis
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q16548
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18734.06

構造登録者

Seo, H.-S.,Dhe-Paganon, S. (登録日: 2017-07-17, 公開日: 2018-01-17, 最終更新日: 2023-10-04)

主引用文献

Harvey, E.P.,Seo, H.S.,Guerra, R.M.,Bird, G.H.,Dhe-Paganon, S.,Walensky, L.D.
Crystal Structures of Anti-apoptotic BFL-1 and Its Complex with a Covalent Stapled Peptide Inhibitor.
Structure, 26:153-160.e4, 2018

PubMed Abstract: BCL-2 family proteins are high-priority cancer targets whose structures provide essential blueprints for drug design. Whereas numerous structures of anti-apoptotic BCL-2 protein complexes with α-helical BH3 peptides have been reported, the corresponding panel of apo structures remains incomplete. Here, we report the crystal structure of apo BFL-1 at 1.69-Å resolution, revealing similarities and key differences among unliganded anti-apoptotic proteins. Unlike all other BCL-2 proteins, apo BFL-1 contains a surface-accessible cysteine within its BH3-binding groove, allowing for selective covalent targeting by a NOXA BH3-based stapled peptide inhibitor. The crystal structure of this complex demonstrated the sulfhydryl bond and fortuitous interactions between the acrylamide-bearing moiety and a newly formed hydrophobic cavity. Comparison of the apo and BH3-liganded structures further revealed an induced conformational change. The two BFL-1 structures expand our understanding of the surface landscapes available for therapeutic targeting so that the apoptotic blockades of BFL-1-dependent cancers can be overcome.

PubMed: 29276033
DOI: 10.1016/j.str.2017.11.016

実験手法

X-RAY DIFFRACTION (1.69 Å)