cAMP-dependent allostery and dynamics in Epac: An NMR view

Rajeevan Selvaratnam, Madoka Akimoto, Bryan VanSchouwen, Giuseppe Melacini

Research output: Contribution to journalReview articlepeer-review

19 Scopus citations


Epac (exchange protein directly activated by cAMP) is a critical cAMP receptor, which senses cAMP and couples the cAMP signal to the catalysis of guanine exchange in the Rap substrate. In the present paper, we review the NMR studies that we have undertaken on the CBD (cyclic-nucleotide-binding domain) of Epac1. Our NMR investigations have shown that cAMP controls distal autoinhibitory interactions through long-range modulations in dynamics. Such dynamically mediated allosteric effects contribute not only to the cAMP-dependent activation of Epac, but also to the selectivity of Epac for cAMP in contrast with cGMP. In addition, we have mapped the interaction networks that couple the cAMP-binding site to the sites involved in the autoinhibitory interactions, using a method based on the covariance analysis of NMR chemical shifts. We anticipate that this approach is generally applicable to dissect allosteric networks in signalling domains.

Original languageEnglish (US)
Pages (from-to)219-223
Number of pages5
JournalBiochemical Society transactions
Issue number1
StatePublished - Feb 2012


  • Allostery
  • Chemical shift covariance analysis (CHESCA)
  • Exchange protein directly activated by cAMP (Epac)
  • Nuclear magnetic resonance (NMR)
  • Protein dynamics
  • cAMP
  • cGMP


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