8H7H

The crystal structure of human abl1 kinase domain in complex with abl1-A-EBA

8H7H の概要

• エントリーDOI: 10.2210/pdb8h7h/pdb
• 分子名称: Tyrosine-protein kinase ABL1, 5-[3-(6-methoxyisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-methyl-N-prop-2-ynyl-pyridine-3-carboxamide (3 entities in total)
• 機能のキーワード: complex, inhibitor, lysine, transferase
• 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: 65020.16

構造登録者

Zhu, C.J.,Zhang, Z.M. (登録日: 2022-10-20, 公開日: 2023-03-22, 最終更新日: 2024-02-07)

主引用文献

Chen, P.,Tang, G.,Zhu, C.,Sun, J.,Wang, X.,Xiang, M.,Huang, H.,Wang, W.,Li, L.,Zhang, Z.M.,Gao, L.,Yao, S.Q.
2-Ethynylbenzaldehyde-Based, Lysine-Targeting Irreversible Covalent Inhibitors for Protein Kinases and Nonkinases.
J.Am.Chem.Soc., 2023

PubMed Abstract: Lysine-targeting irreversible covalent inhibitors have attracted growing interests in recent years, especially in the fields of kinase research. Despite encouraging progress, few chemistries are available to develop inhibitors that are exclusively lysine-targeting, selective, and cell-active. We report herein a 2-ethynylbenzaldehyde (EBA)-based, lysine-targeting strategy to generate potent and selective small-molecule inhibitors of ABL kinase by selectively targeting the conserved catalytic lysine in the enzyme. We showed the resulting compounds were cell-active, capable of covalently engaging endogenous ABL kinase in K562 cells with long-residence time and few off-targets. We further validated the generality of this strategy by developing EBA-based irreversible inhibitors against EGFR (a kinase) and Mcl-1 (a nonkinase) that covalently reacted with the catalytic and noncatalytic lysine within each target.

PubMed: 36774655
DOI: 10.1021/jacs.2c11595

実験手法

X-RAY DIFFRACTION (2.27789711576 Å)