2. Academic Validation
  3. Hematopoietic Progenitor Kinase-1 Structure in a Domain-Swapped Dimer

Hematopoietic Progenitor Kinase-1 Structure in a Domain-Swapped Dimer

  • Structure. 2019 Jan 2;27(1):125-133.e4. doi: 10.1016/j.str.2018.10.025.
Ping Wu 1,  Christopher J Sneeringer 2,  Keith E Pitts 2,  Eric S Day 3,  Bryan K Chan 4,  Binqing Wei 4,  Isabelle Lehoux 5,  Kyle Mortara 5,  Hong Li 6,  Jiansheng Wu 6,  Yvonne Franke 5,  John G Moffat 2,  Jane L Grogan 7,  Timothy P Heffron 4,  Weiru Wang 8
Affiliations

Affiliations

  • 1 Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA.
  • 2 Department of Biochemical Pharmacology, Genentech, South San Francisco, CA 94080, USA.
  • 3 Department of Late Stage Pharmaceutical Development, Genentech, South San Francisco, CA 94080, USA.
  • 4 Department of Discovery Chemistry, Genentech, South San Francisco, CA 94080, USA.
  • 5 Department of Biomolecular Resources, Genentech, South San Francisco, CA 94080, USA.
  • 6 Department of Protein Chemistry, Genentech, South San Francisco, CA 94080, USA.
  • 7 Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA.
  • 8 Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA. Electronic address: wang.weiru@gene.com.
PMID: 30503777 DOI: 10.1016/j.str.2018.10.025
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.

Keywords

HPK1; X-ray crystallography; cancer; immunology; inhibitor; kinase.

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