title: Tapping the translation potential of cAMP signalling: molecular basis for selectivity in cAMP agonism and antagonism as revealed by NMR.
abstract: Eukaryotic CBDs (cAMP-binding domains) control multiple cellular functions (e.g. phosphorylation, guanine exchange and ion channel gating). Hence the manipulation of cAMP-dependent signalling pathways has a high translational potential. However, the ubiquity of eukaryotic CBDs also poses a challenge in terms of selectivity. Before the full translational potential of cAMP signalling can be tapped, it is critical to understand the structural basis for selective cAMP agonism and antagonism. Recent NMR investigations have shown that structurally homologous CBDs respond differently to several CBD ligands and that these unexpected differences arise at the level of either binding (i.e. affinity) or allostery (i.e. modulation of the autoinhibitory equilibria). In the present article, we specifically address how the highly conserved CBD fold binds cAMP with markedly different affinities in PKA (protein kinase A) relative to other eukaryotic cAMP receptors, such as Epac (exchange protein directly activated by cAMP) and HCN (hyperpolarization-activated cyclic-nucleotide-modulated channel). A major emerging determinant of cAMP affinity is hypothesized to be the position of the autoinhibitory equilibrium of the apo-CBD, which appears to vary significantly across different CBDs. These analyses may assist the development of selective CBD effectors that serve as potential drug leads for the treatment of cardiovascular diseases.
authors.affiliation: *Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1.
authors.forename: Stephen
authors.initials: S
authors.lastname: Boulton
authors.affiliation: †Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1.
authors.forename: Madoka
authors.initials: M
authors.lastname: Akimoto
authors.affiliation: †Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1.
authors.forename: Bryan
authors.initials: B
authors.lastname: VanSchouwen
authors.affiliation: †Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1.
authors.forename: Kody
authors.initials: K
authors.lastname: Moleschi
authors.affiliation: †Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1.
authors.forename: Rajeevan
authors.initials: R
authors.lastname: Selvaratnam
authors.affiliation: †Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1.
authors.forename: Rajanish
authors.initials: R
authors.lastname: Giri
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Melacini
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases