Elastic network normal mode dynamics reveal the GPCR activation mechanism

Dikla Kolan, Gennadiy Fonar, Abraham O. Samson

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


G-protein-coupled receptors (GPCR) are a family of membrane-embedded metabotropic receptors which translate extracellular ligand binding into an intracellular response. Here, we calculate the motion of several GPCR family members such as the M2 and M3 muscarinic acetylcholine receptors, the A2A adenosine receptor, the β2-adrenergic receptor, and the CXCR4 chemokine receptor using elastic network normal modes. The normal modes reveal a dilation and a contraction of the GPCR vestibule associated with ligand passage, and activation, respectively. Contraction of the vestibule on the extracellular side is correlated with cavity formation of the G-protein binding pocket on the intracellular side, which initiates intracellular signaling. Interestingly, the normal modes of rhodopsin do not correlate well with the motion of other GPCR family members. Electrostatic potential calculation of the GPCRs reveal a negatively charged field around the ligand binding site acting as a siphon to draw-in positively charged ligands on the membrane surface. Altogether, these results expose the GPCR activation mechanism and show how conformational changes on the cell surface side of the receptor are allosterically translated into structural changes on the inside.

Original languageEnglish
Pages (from-to)579-586
Number of pages8
JournalProteins: Structure, Function and Bioinformatics
Issue number4
StatePublished - Apr 2014

Bibliographical note

Grant sponsor: Marie-Curie CIG; Grant number: 322113; Grant sponsor: Katz Foundation.


  • Adenosine
  • Adrenergic
  • CXCR4
  • G-protein-coupled receptor
  • GPCR
  • Muscarinic
  • Normal modes


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