Transforming PKA into PKG – a structure-function approach to understand cyclic nucleotide selectivity

Abstract

Background cAMP-dependent protein kinase (PKA) and cGMPdependent protein kinase (PKG) are the main effectors of distinct cyclic nucleotide pathways and are preferentially activated by cAMP or cGMP, respectively. We recently characterized the isolated C-terminal cyclic nucleotide binding domain (CNB-B) of the human PKG Ib as highly cGMP-selective (manuscript in preparation). In a crystal structure of the CNB-B two novel cGMP-specific interaction sites were identified in addition to the previously described threonine residue (T317) in the phosphate binding cassette [1]. Mutation of each individual site resulted in reduced cGMP-selectivity and interfered with cGMP-dependent activation of PKG Ib. To gain further insight into the molecular basis of cyclic nucleotide selectivity, we inserted two cGMP-specific interaction sites into the CNB-B of human PKA RIa by mutating corresponding residues. We hypothesize that this way cGMP-specific interaction contacts can be created in PKA and thereby modulate cAMP-selectivity [1,2].

DOI: 10.1186/2050-6511-14-S1-P41

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@inproceedings{Lorenz2013TransformingPI, title={Transforming PKA into PKG – a structure-function approach to understand cyclic nucleotide selectivity}, author={Robin G. Lorenz and Eui-Whan Moon and Gilbert Y Huang and Albert S. Reger and Jeong Joo Kim and Eugen Franz and Daniela Bertinetti and Choel Kim and Friedrich W Herberg}, booktitle={BMC Pharmacology and Toxicology}, year={2013} }