6L8L

C-Src in complex with ibrutinib

6L8L の概要

• エントリーDOI: 10.2210/pdb6l8l/pdb
• 分子名称: Proto-oncogene tyrosine-protein kinase Src, 1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one (3 entities in total)
• 機能のキーワード: kinase, transferase
• 由来する生物種: Gallus gallus (Chicken)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 132668.57

構造登録者

Guo, M.,Dai, S.,Chen, L.,Chen, Y. (登録日: 2019-11-06, 公開日: 2020-11-11, 最終更新日: 2023-11-22)

主引用文献

Guo, M.,Dai, S.,Wu, D.,Duan, Y.,Li, J.,Qu, L.,Jiang, L.,Chen, Z.,Chen, X.,Chen, Y.
Characterization of ibrutinib as a non-covalent inhibitor of SRC-family kinases.
Bioorg.Med.Chem.Lett., 34:127757-127757, 2020

PubMed Abstract: Ibrutinib is a BTK-targeted irreversible inhibitor. In this study, we demonstrate that ibrutinib potently inhibits SRC activity in a non-covalent manner via mass spectrometry and crystallography. The S345C mutation renders SRC to bind covalently with ibrutinib, and restores the potency of ibrutinib against the gatekeeper mutant. The co-crystal structure of ibrutinib/SRC shows Ser345 of SRC did not form covalent bond with ibrutinib, leading to a decrease of potency and loss of the ability to overcome the gatekeeper mutation of SRC. The X-ray crystallographic studies also provide structural insight into why ibrutinib behaves differently against gatekeeper mutants of different kinases.

PubMed: 33359446
DOI: 10.1016/j.bmcl.2020.127757

実験手法

X-RAY DIFFRACTION (2.888 Å)