Journal of Molecular Modeling

, Volume 18, Issue 9, pp 4053–4060 | Cite as

A novel dimerization interface of cyclic nucleotide binding domain, which is disrupted in presence of cAMP: implications for CNG channels gating

  • Ivan Y. Gushchin
  • Valentin I. Gordeliy
  • Sergei GrudininEmail author
Original Paper


Cyclic nucleotide binding domain (CNBD) is a ubiquitous domain of effector proteins involved in signalling cascades of prokaryota and eukaryota. CNBD activation by cyclic nucleotide monophosphate (cNMP) is studied well in the case of several proteins. However, this knowledge is hardly applicable to cNMP-modulated cation channels. Despite the availability of CNBD crystal structures of bacterial cyclic nucleotide-gated (CNG) and mammalian hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels in presence and absence of the cNMP, the full understanding of CNBD conformational changes during activation is lacking. Here, we describe a novel CNBD dimerization interface found in crystal structures of bacterial CNG channel MlotiK1 and mammalian cAMP-activated guanine nucleotide-exchange factor Epac2. Molecular dynamics simulations show that the found interface is stable on the studied timescale of 100 ns, in contrast to the dimerization interface, reported previously. Comparisons with cN-bound structures of CNBD show that the dimerization is incompatible with cAMP binding. Thus, the cAMP-dependent monomerization of CNBD may be an alternative mechanism of the cAMP sensing. Based on these findings, we propose a model of the bacterial CNG channel modulation by cAMP.


Model of the bacterial CNG channel activation by cAMP


Channel gating CNG channel Cyclic-nucleotide binding domain Epac2 



Cyclic nucleotide binding domain


Cyclic nucleotide monophosphate


Cyclic adenosine monophosphate


Channel, cyclic nucleotide-gated channel


Channel, hyperpolarization-activated cyclic nucleotide-modulated channel


Molecular dynamics


Root mean square deviation


Principal components analysis



This work was supported by the program "Chaires d'excellence" edition 2008 of the Agence National de la Recherche France, Commissariat a l’Energie atomique (Institut de Biologie Structurale) – Helmholtz Association (Forschungszentrum Juelich) Specific Topic of Cooperation agreement 5.1, the Marie Curie grant for training and career development of researchers (FP7-PEOPLE-2007-1-1-ITN, project Structural Biology of Membrane Proteins) and by an European Commission 7th Framework Programme grant for the EDICT (European Drug Initiative on Channels and Transporters) consortium (HEALTH-201924). This work was done in the framework of Russian State Contracts № 02.740.11.0299, № 02.740.11.5010 and №P974 in the framework of activity 1.2.2 of the Federal Target Program «Scientific and academic research cadres of innovative Russia» for 2009–2013 years. Part of this work was supported by the German Federal Ministry of Education and Research (PhoNa – Photonic Nanomaterials). Partial financial support from Onexim group is gratefully acknowledged. Part of the simulations were conducted on the Juropa supercomputer at Forschungszentrum Juelich.


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Ivan Y. Gushchin
    • 1
    • 2
    • 3
    • 4
  • Valentin I. Gordeliy
    • 1
    • 2
    • 3
    • 4
    • 5
  • Sergei Grudinin
    • 6
    • 7
    Email author
  1. 1.Institut de Biologie Structurale Jean-Pierre EbelUniversité Joseph Fourier – Grenoble 1GrenobleFrance
  2. 2.Institut de Biologie Structurale Jean-Pierre EbelCEAGrenobleFrance
  3. 3.Institut de Biologie Structurale Jean-Pierre EbelCNRSGrenobleFrance
  4. 4.Research-educational Centre “Bionanophysics”Moscow Institute of Physics and TechnologyDolgoprudniyRussia
  5. 5.Institute of Complex Systems (ICS), ICS-5: Molecular BiophysicsResearch Centre JuelichJuelichGermany
  6. 6.NANO-DINRIA Grenoble-Rhone-Alpes Research CenterSaint Ismier CedexFrance
  7. 7.CNRS, Laboratoire Jean KuntzmannGrenoble Cedex 9France

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