Universality of the Sodium Ion Binding Mechanism in Class A G-Protein-Coupled Receptors

Balaji Selvam, Zahra Shamsi, Diwakar Shukla

Research output: Contribution to journalArticlepeer-review


The allosteric modulation of G-protein-coupled receptors (GPCRs) by sodium ions has received significant attention as crystal structures of several receptors show Na+ ions bound to the inactive conformations at the conserved Asp2.50. To date, structures from 24 families of GPCRs have been determined, though mechanistic insights into Na+ binding to the allosteric site are limited. We performed hundreds-of-microsecond long simulations of 18 GPCRs and elucidated their Na+ binding mechanism. In class A GPCRs, the Na+ ion binds to the conserved residue 2.50 whereas in class B receptors, it binds at 3.43b, 6.53b, and 7.49b. Using Markov state models, we obtained the free energy profiles and kinetics of Na+ binding to the allosteric site, which reveal a conserved mechanism of Na+ binding for GPCRs and show the residues that act as major barriers for ion diffusion. Furthermore, we also show that the Na+ ion can bind to GPCRs from the intracellular side when the allosteric site is inaccessible from the extracellular side.

Original languageEnglish (US)
Pages (from-to)3048-3053
Number of pages6
JournalAngewandte Chemie - International Edition
Issue number12
StatePublished - Mar 12 2018


  • G-protein-coupled receptors
  • allosteric modulators
  • molecular dynamics
  • signal transduction
  • sodium

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry


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