7OTE

Src Kinase Domain in complex with ponatinib

7OTE の概要

• エントリーDOI: 10.2210/pdb7ote/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, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (5 entities in total)
• 機能のキーワード: atp inhibitor, kinase, ligand binding, cell signalling, oncoprotein
• 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: 69279.08

構造登録者

Soriano-Maldonado, P.,Cuesta-Hernandez, H.N.,Plaza-Menacho, I. (登録日: 2021-06-10, 公開日: 2022-06-22, 最終更新日: 2024-03-27)

主引用文献

Cuesta-Hernandez, H.N.,Contreras, J.,Soriano-Maldonado, P.,Sanchez-Wandelmer, J.,Yeung, W.,Martin-Hurtado, A.,Munoz, I.G.,Kannan, N.,Llimargas, M.,Munoz, J.,Plaza-Menacho, I.
An allosteric switch between the activation loop and a c-terminal palindromic phospho-motif controls c-Src function.
Nat Commun, 14:6548-6548, 2023

PubMed Abstract: Autophosphorylation controls the transition between discrete functional and conformational states in protein kinases, yet the structural and molecular determinants underlying this fundamental process remain unclear. Here we show that c-terminal Tyr 530 is a de facto c-Src autophosphorylation site with slow time-resolution kinetics and a strong intermolecular component. On the contrary, activation-loop Tyr 419 undergoes faster kinetics and a cis-to-trans phosphorylation switch that controls c-terminal Tyr 530 autophosphorylation, enzyme specificity, and strikingly, c-Src non-catalytic function as a substrate. In line with this, we visualize by X-ray crystallography a snapshot of Tyr 530 intermolecular autophosphorylation. In an asymmetric arrangement of both catalytic domains, a c-terminal palindromic phospho-motif flanking Tyr 530 on the substrate molecule engages the G-loop of the active kinase adopting a position ready for entry into the catalytic cleft. Perturbation of the phospho-motif accounts for c-Src dysfunction as indicated by viral and colorectal cancer (CRC)-associated c-terminal deleted variants. We show that c-terminal residues 531 to 536 are required for c-Src Tyr 530 autophosphorylation, and such a detrimental effect is caused by the substrate molecule inhibiting allosterically the active kinase. Our work reveals a crosstalk between the activation and c-terminal segments that control the allosteric interplay between substrate- and enzyme-acting kinases during autophosphorylation.

PubMed: 37848415
DOI: 10.1038/s41467-023-41890-7

実験手法

X-RAY DIFFRACTION (2.49 Å)