6CQE

Crystal structure of HPK1 kinase domain S171A mutant

Summary for 6CQE

• Entry DOI: 10.2210/pdb6cqe/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase kinase 1 (2 entities in total)
• Functional Keywords: protein kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 65952.56

Authors

Wu, P.,Lehoux, I.,Mortara, K.,Franke, Y.,Wang, W. (deposition date: 2018-03-15, release date: 2018-12-19, Last modification date: 2024-03-13)

Primary citation

Wu, P.,Sneeringer, C.J.,Pitts, K.E.,Day, E.S.,Chan, B.K.,Wei, B.,Lehoux, I.,Mortara, K.,Li, H.,Wu, J.,Franke, Y.,Moffat, J.G.,Grogan, J.L.,Heffron, T.P.,Wang, W.
Hematopoietic Progenitor Kinase-1 Structure in a Domain-Swapped Dimer.
Structure, 27:125-133.e4, 2019

PubMed Abstract: Enhancement of antigen-specific T cell immunity has shown significant therapeutic benefit in infectious diseases and cancer. Hematopoietic progenitor kinase-1 (HPK1) is a negative-feedback regulator of T cell receptor signaling, which dampens T cell proliferation and effector function. A recent report showed that a catalytic dead mutant of HPK1 phenocopies augmented T cell responses observed in HPK1-knockout mice, indicating that kinase activity is critical for function. We evaluated active and inactive mutants and determined crystal structures of HPK1 kinase domain (HPK1-KD) in apo and ligand bound forms. In all structures HPK1-KD displays a rare domain-swapped dimer, in which the activation segment comprises a well-conserved dimer interface. Biophysical measurements show formation of dimer in solution. The activation segment adopts an α-helical structure which exhibits distinct orientations in active and inactive states. This face-to-face configuration suggests that the domain-swapped dimer may possess alternative selectivity for certain substrates of HPK1 under relevant cellular context.

PubMed: 30503777
DOI: 10.1016/j.str.2018.10.025

Experimental method

X-RAY DIFFRACTION (1.886 Å)