6FTF
Regulatory subunit of a cAMP-independent protein kinase A from Trypanosoma cruzi at 1.09 A resolution
Summary for 6FTF
| Entry DOI | 10.2210/pdb6ftf/pdb |
| Descriptor | Protein kinase A regulatory subunit, putative, 1,2-ETHANEDIOL, 7-cyano-7-deazainosine, ... (4 entities in total) |
| Functional Keywords | protein kinase a, regulatory subunit, cell signalling, signaling protein |
| Biological source | Trypanosoma cruzi (strain CL Brener) |
| Total number of polymer chains | 1 |
| Total formula weight | 35246.76 |
| Authors | Volpato Santos, Y.,Lorentzen, E.,Basquin, J.,Boshart, M. (deposition date: 2018-02-21, release date: 2019-04-03, Last modification date: 2024-01-17) |
| Primary citation | Bachmaier, S.,Volpato Santos, Y.,Kramer, S.,Githure, G.B.,Klockner, T.,Pepperl, J.,Baums, C.,Schenk, R.,Schwede, F.,Genieser, H.G.,Dupuy, J.W.,Forne, I.,Imhof, A.,Basquin, J.,Lorentzen, E.,Boshart, M. Nucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma. Nat Commun, 10:1421-1421, 2019 Cited by PubMed 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 ≥ 6.5 nM) and high affinity ligands (K ≥ 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. PubMed: 30926779DOI: 10.1038/s41467-019-09338-z PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.09151939067 Å) |
Structure validation
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