6FTF

Regulatory subunit of a cAMP-independent protein kinase A from Trypanosoma cruzi at 1.09 A resolution

6FTF の概要

• エントリーDOI: 10.2210/pdb6ftf/pdb
• 分子名称: Protein kinase A regulatory subunit, putative, 1,2-ETHANEDIOL, 7-cyano-7-deazainosine, ... (4 entities in total)
• 機能のキーワード: protein kinase a, regulatory subunit, cell signalling, signaling protein
• 由来する生物種: Trypanosoma cruzi (strain CL Brener)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35246.76

構造登録者

Volpato Santos, Y.,Lorentzen, E.,Basquin, J.,Boshart, M. (登録日: 2018-02-21, 公開日: 2019-04-03, 最終更新日: 2024-01-17)

主引用文献

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

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: 30926779
DOI: 10.1038/s41467-019-09338-z

実験手法

X-RAY DIFFRACTION (1.09151939067 Å)