Conformational plasticity of the ULK3 kinase domain

Biochem J. 2021 Jul 30;478(14):2811-2823. doi: 10.1042/BCJ20210257.

Abstract

The human protein kinase ULK3 regulates the timing of membrane abscission, thus being involved in exosome budding and cytokinesis. Herein, we present the first high-resolution structures of the ULK3 kinase domain. Its unique features are explored against the background of other ULK kinases. An inhibitor fingerprint indicates that ULK3 is highly druggable and capable of adopting a wide range of conformations. In accordance with this, we describe a conformational switch between the active and an inactive ULK3 conformation, controlled by the properties of the attached small-molecule binder. Finally, we discuss a potential substrate-recognition mechanism of the full-length ULK3 protein.

Keywords: ULK kinase; conformational changes; enzyme–substrate interactions; phosphorylation; small-molecule inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / metabolism
  • Aniline Compounds / pharmacology
  • Benzamides / metabolism
  • Benzamides / pharmacology
  • Biocatalysis / drug effects
  • Catalytic Domain*
  • Humans
  • Models, Molecular
  • Nitriles / metabolism
  • Nitriles / pharmacology
  • Oncogene Proteins / chemistry
  • Oncogene Proteins / metabolism
  • Protein Binding
  • Protein Conformation*
  • Protein Domains*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / chemistry*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology
  • Quinolines / metabolism
  • Quinolines / pharmacology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Substrate Specificity

Substances

  • Aniline Compounds
  • Benzamides
  • IST1 protein, human
  • Nitriles
  • Oncogene Proteins
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Quinolines
  • Recombinant Proteins
  • bosutinib
  • N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
  • Protein-Serine-Threonine Kinases
  • ULK3 protein, human