Tapping the translation potential of cAMP signalling: Molecular basis for selectivity in cAMP agonism and antagonism as revealed by NMR

Stephen Boulton, Madoka Akimoto, Bryan VanSchouwen, Kody Moleschi, Rajeevan Selvaratnam, Rajanish Giri, Giuseppe Melacini

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)302-307
Number of pages6
JournalBiochemical Society Transactions
Volume42
Issue number2
DOIs
Publication statusPublished - 2014 Apr

Keywords

  • Exchange protein directly activated by cAMP (Epac)
  • Hyperpolarization-activated cyclic-nucleotide-modulated channel (HCN)
  • Protein kinase A (PKA)
  • Selectivity
  • Signalling
  • cAMP

ASJC Scopus subject areas

  • Biochemistry

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