6cqf
From Proteopedia
Crystal structure of HPK1 in complex an inhibitor G1858
Structural highlights
Function[M4K1_HUMAN] Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate.[1] [2] Publication Abstract from PubMedEnhancement 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 alpha-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. Hematopoietic Progenitor Kinase-1 Structure in a Domain-Swapped Dimer.,Wu P, Sneeringer CJ, Pitts KE, Day ES, Chan BK, Wei B, Lehoux I, Mortara K, Li H, Wu J, Franke Y, Moffat JG, Grogan JL, Heffron TP, Wang W Structure. 2018 Nov 13. pii: S0969-2126(18)30386-1. doi:, 10.1016/j.str.2018.10.025. PMID:30503777[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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