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

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 (K_D ≥ 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 doma

SUBMITTER: Bachmaier S 

PROVIDER: S-EPMC6440977 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature