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Nucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma.
- Source :
-
Nature communications [Nat Commun] 2019 Mar 29; Vol. 10 (1), pp. 1421. Date of Electronic Publication: 2019 Mar 29. - Publication Year :
- 2019
-
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 (EC <subscript>50</subscript> ≥ 6.5 nM) and high affinity ligands (K <subscript>D</subscript> ≥ 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.
- Subjects :
- Amino Acid Sequence
Crystallography, X-Ray
Cyclic AMP metabolism
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit chemistry
Dipyridamole pharmacology
Drug Evaluation, Preclinical
Enzyme Activators chemistry
Holoenzymes metabolism
Leishmania drug effects
Molecular Docking Simulation
Phosphorylation drug effects
Signal Transduction
Trypanosoma brucei brucei drug effects
Tubercidin pharmacology
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit metabolism
Enzyme Activators pharmacology
Nucleosides analogs & derivatives
Trypanosoma brucei brucei enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 30926779
- Full Text :
- https://doi.org/10.1038/s41467-019-09338-z