title: Mechanism of cAMP Partial Agonism in Protein Kinase G (PKG).
abstract: Protein kinase G (PKG) is a major receptor of cGMP and controls signaling pathways often distinct from those regulated by cAMP. Hence, the selective activation of PKG by cGMP versus cAMP is critical. However, the mechanism of cGMP-versus-cAMP selectivity is only limitedly understood. Although the C-terminal cyclic nucleotide-binding domain B of PKG binds cGMP with higher affinity than cAMP, the intracellular concentrations of cAMP are typically higher than those of cGMP, suggesting that the cGMP-versus-cAMP selectivity of PKG is not controlled uniquely through affinities. Here, we show that cAMP is a partial agonist for PKG, and we elucidate the mechanism for cAMP partial agonism through the comparative NMR analysis of the apo, cGMP-, and cAMP-bound forms of the PKG cyclic nucleotide-binding domain B. We show that although cGMP activation is adequately explained by a two-state conformational selection model, the partial agonism of cAMP arises from the sampling of a third, partially autoinhibited state.
authors.affiliation: From the Departments of Chemistry and Chemical Biology and.
authors.forename: Bryan
authors.initials: B
authors.lastname: VanSchouwen
authors.affiliation: From the Departments of Chemistry and Chemical Biology and.
authors.forename: Rajeevan
authors.initials: R
authors.lastname: Selvaratnam
authors.affiliation: From the Departments of Chemistry and Chemical Biology and.
authors.forename: Rajanish
authors.initials: R
authors.lastname: Giri
authors.affiliation: the Department of Biochemistry, Kassel University, Heinrich Plett Strasse 40, 34132 Kassel, Germany, and.
authors.forename: Robin
authors.initials: R
authors.lastname: Lorenz
authors.affiliation: the Department of Biochemistry, Kassel University, Heinrich Plett Strasse 40, 34132 Kassel, Germany, and.
authors.forename: Friedrich W
authors.initials: FW
authors.lastname: Herberg
authors.affiliation: the Verna and Marrs McLean Department of Biochemistry and Molecular Biology and Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Choel
authors.initials: C
authors.lastname: Kim
authors.affiliation: From the Departments of Chemistry and Chemical Biology and Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4M1, Canada, melacin@mcmaster.ca.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Melacini
mesh_terms: D000242:Cyclic AMP / Q000737:chemistry*; D006152:Cyclic GMP / Q000737:chemistry*; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
chemical_list: D000242:Cyclic AMP; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D006152:Cyclic GMP
keywords: agonism; allosteric regulation; cell signaling; cyclic AMP (cAMP); cyclic GMP (cGMP); molecular dynamics; nuclear magnetic resonance (NMR); protein kinase G (PKG)