6L8L

C-Src in complex with ibrutinib

Summary for 6L8L

• Entry DOI: 10.2210/pdb6l8l/pdb
• Descriptor: 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)
• Functional Keywords: kinase, transferase
• Biological source: Gallus gallus (Chicken)
• Total number of polymer chains: 4
• Total formula weight: 132668.57

Authors

Guo, M.,Dai, S.,Chen, L.,Chen, Y. (deposition date: 2019-11-06, release date: 2020-11-11, Last modification date: 2023-11-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.888 Å)