7KP6

Structure of Ack1 kinase in complex with a selective inhibitor

7KP6 の概要

• エントリーDOI: 10.2210/pdb7kp6/pdb
• 分子名称: Activated CDC42 kinase 1, 5-chloro-N~2~-[4-(4-methylpiperazin-1-yl)phenyl]-N~4~-{[(2R)-oxolan-2-yl]methyl}pyrimidine-2,4-diamine, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: protein-inhibitor complex, tyrosine kinase, transferase, transferase-inhibitor complex, transferase/inhibitor
• 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: 65867.64

構造登録者

Thakur, M.K.,Miller, W.T.,Mahajan, N.,Seeliger, M.A. (登録日: 2020-11-10, 公開日: 2022-02-09, 最終更新日: 2023-10-25)

主引用文献

Sridaran, D.,Chouhan, S.,Mahajan, K.,Renganathan, A.,Weimholt, C.,Bhagwat, S.,Reimers, M.,Kim, E.H.,Thakur, M.K.,Saeed, M.A.,Pachynski, R.K.,Seeliger, M.A.,Miller, W.T.,Feng, F.Y.,Mahajan, N.P.
Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance.
Nat Commun, 13:6929-6929, 2022

PubMed Abstract: Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK Y18-phosphorylation and spontaneous activation of CD8 and CD4 T cells, resulting in inhibited growth of transplanted ICB-resistant tumours. Furthermore, ICB treatment of castration-resistant prostate cancer (CRPC) patients results in re-activation of ACK1/pY18-CSK signalling, confirming the involvement of this pathway in ICB insensitivity. An ACK1 small-molecule inhibitor, (R)-9b, recapitulates inhibition of ICB-resistant tumours, which provides evidence for ACK1 enzymatic activity playing a pivotal role in generating ICB resistance. Overall, our study identifies an important mechanism of ICB resistance and holds potential for expanding the scope of ICB therapy to tumours that are currently unresponsive.

PubMed: 36376335
DOI: 10.1038/s41467-022-34724-5

実験手法

X-RAY DIFFRACTION (1.79 Å)