7KP6

Structure of Ack1 kinase in complex with a selective inhibitor

Summary for 7KP6

• Entry DOI: 10.2210/pdb7kp6/pdb
• Descriptor: 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)
• Functional Keywords: protein-inhibitor complex, tyrosine kinase, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 65867.64

Authors

Thakur, M.K.,Miller, W.T.,Mahajan, N.,Seeliger, M.A. (deposition date: 2020-11-10, release date: 2022-02-09, Last modification date: 2023-10-25)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.79 Å)