9LI8

Crystal structure of Bcl-xL in complex with HRK BH3 peptide

9LI8 の概要

• エントリーDOI: 10.2210/pdb9li8/pdb
• 分子名称: Bcl-2-like protein 1, Activator of apoptosis harakiri (3 entities in total)
• 機能のキーワード: bcl-2 family, mitochondrial apoptosis, bh3-only proteins, apoptosis
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 27275.05

構造登録者

Wei, H.,Guo, M.,Wang, J. (登録日: 2025-01-13, 公開日: 2025-08-06, 最終更新日: 2025-09-17)

主引用文献

Wang, J.,Guo, M.,Dai, S.,Wei, H.
Molecular mechanisms underlying HRK interaction with BCL-XL and BCL-2 reveal specificity determinants for BH3 mimetics.
Iscience, 28:113309-113309, 2025

PubMed Abstract: BH3 mimetics targeting the BCL-2 family hold broad promise for cancer therapy. High similarity between the anti-apoptotic proteins BCL-XL and BCL-2 challenges the engineering of selective inhibitors. The BH3-only protein HRK is a natural selective inhibitor of BCL-XL and to a less extent of BCL-2. The detailed interaction mechanism remains elusive. Our structural and mutational analyses show that the discrepant conformational changes and non-conserved residues in the α2-α3 region are crucial for the preferential binding between BCL-XL and HRK. BCL-XL tolerates hydrophilic Thr33 or hydrophobic substitutions at the h1 position of HRK, whereas BCL-2 favors hydrophobic interactions, resulting in a weaker affinity for HRK. In addition, we design HRK-derived stapled peptides with improved helicity and activity against BCL-XL and BCL-2, and further elucidate the structural mechanism. Our findings reveal the binding specificity of HRK interactions with BCL-XL and BCL-2, and provide advanced insights into the development of BH3 mimetics.

PubMed: 40894900
DOI: 10.1016/j.isci.2025.113309

実験手法

X-RAY DIFFRACTION (2.32 Å)