7WF5

c-Src in complex with ponatinib

7WF5 の概要

• エントリーDOI: 10.2210/pdb7wf5/pdb
• 分子名称: Proto-oncogene tyrosine-protein kinase Src, 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide (3 entities in total)
• 機能のキーワード: inhibitor, kinase, oncoprotein
• 由来する生物種: Gallus gallus (chicken)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66518.41

構造登録者

Guo, M.,Duan, Y.,Dai, S.,Chen, X.,Chen, Y. (登録日: 2021-12-26, 公開日: 2022-03-02, 最終更新日: 2023-11-29)

主引用文献

Guo, M.,Duan, Y.,Dai, S.,Li, J.,Chen, X.,Qu, L.,Chen, Z.,Wei, H.,Jiang, L.,Chen, Y.
Structural study of ponatinib in inhibiting SRC kinase.
Biochem.Biophys.Res.Commun., 598:15-19, 2022

PubMed Abstract: Ponatinib is a multi-target tyrosine kinase inhibitor that targets ABL, SRC, FGFR, and so on. It was designed to overcome the resistance of BCR-ABL mutation to imatinib, especially the gatekeeper mutation ABL. The molecular mechanism by which ponatinib overcomes mutations of BCR-ABL and some other targets has been explained, but little information is known about the characteristics of ponatinib binding to SRC. Here, we showed that ponatinib inhibited wild type SRC kinase but failed to inhibit SRC gatekeeper mutants in both biochemical and cellular assays. We determined the crystal structure of ponatinib in complex with the SRC kinase domain. In addition, by structural analysis, we provided a possible explanation for why ponatinib showed different effects on SRC and other kinases with gatekeeper mutations. The resistance mechanism of SRC gatekeeper mutations to ponatinib may provide meaningful information for designing inhibitors against SRC family kinases in the future.

PubMed: 35151199
DOI: 10.1016/j.bbrc.2022.02.001

実験手法

X-RAY DIFFRACTION (1.798 Å)