2. Academic Validation
  3. Nucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma

Nucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma

  • Nat Commun. 2019 Mar 29;10(1):1421. doi: 10.1038/s41467-019-09338-z.
Sabine Bachmaier 1,  Yuri Volpato Santos 1,  Susanne Kramer 1 2,  George Boniface Githure 1,  Thomas Klöckner 1,  Julia Pepperl 1,  Cordula Baums 1,  Robin Schenk 1,  Frank Schwede 3,  Hans-Gottfried Genieser 3,  Jean-William Dupuy 4,  Ignasi Forné 5,  Axel Imhof 5,  Jerôme Basquin 6,  Esben Lorentzen 7,  Michael Boshart 8
Affiliations

Affiliations

  • 1 Biocenter, Faculty of Biology, Genetics, Ludwig-Maximilians-University Munich (LMU), 82152, Martinsried, Germany.
  • 2 Department of Cell & Developmental Biology, Biocenter, University of Würzburg, Würzburg, 97074, Germany.
  • 3 BIOLOG Life Science Institute, 28199, Bremen, Germany.
  • 4 Centre de Génomique Fonctionnelle Bordeaux, Université Bordeaux, F-33076, Bordeaux, France.
  • 5 Biomedical Center, Ludwig-Maximilians-University Munich (LMU), 82152, Martinsried, Germany.
  • 6 Max Planck-Institute for Biochemistry, 82152, Martinsried, Germany.
  • 7 Department of Molecular Biology and Genetics, Aarhus University, Aarhus, 8000, Denmark.
  • 8 Biocenter, Faculty of Biology, Genetics, Ludwig-Maximilians-University Munich (LMU), 82152, Martinsried, Germany. boshart@lmu.de.
PMID: 30926779 DOI: 10.1038/s41467-019-09338-z
Abstract

Protein kinase A (PKA), the main effector of cAMP in eukaryotes, is a paradigm for the mechanisms of ligand-dependent and allosteric regulation in signalling. Here we report the orthologous but cAMP-independent PKA of the protozoan Trypanosoma and identify 7-deaza-nucleosides as potent activators (EC50 ≥ 6.5 nM) and high affinity ligands (KD ≥ 8 nM). A co-crystal structure of trypanosome PKA with 7-cyano-7-deazainosine and molecular docking show how substitution of key Amino acids in both CNB domains of the regulatory subunit and its unique C-terminal αD helix account for this ligand swap between trypanosome PKA and canonical cAMP-dependent PKAs. We propose nucleoside-related endogenous activators of Trypanosoma brucei PKA (TbPKA). The existence of eukaryotic CNB domains not associated with binding of cyclic nucleotides suggests that orphan CNB domains in other eukaryotes may bind undiscovered signalling molecules. Phosphoproteome analysis validates 7-cyano-7-deazainosine as powerful cell-permeable inducer to explore cAMP-independent PKA signalling in medically important neglected pathogens.

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