Universal allosteric mechanism for Gα activation by GPCRs

Nature. 2015 Aug 13;524(7564):173-179. doi: 10.1038/nature14663. Epub 2015 Jul 6.


G protein-coupled receptors (GPCRs) allosterically activate heterotrimeric G proteins and trigger GDP release. Given that there are ∼800 human GPCRs and 16 different Gα genes, this raises the question of whether a universal allosteric mechanism governs Gα activation. Here we show that different GPCRs interact with and activate Gα proteins through a highly conserved mechanism. Comparison of Gα with the small G protein Ras reveals how the evolution of short segments that undergo disorder-to-order transitions can decouple regions important for allosteric activation from receptor binding specificity. This might explain how the GPCR-Gα system diversified rapidly, while conserving the allosteric activation mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation*
  • Animals
  • Binding Sites
  • Computational Biology
  • Conserved Sequence
  • Enzyme Activation
  • Evolution, Molecular*
  • GTP-Binding Protein alpha Subunits / chemistry
  • GTP-Binding Protein alpha Subunits / genetics
  • GTP-Binding Protein alpha Subunits / metabolism*
  • Genetic Engineering
  • Guanosine Diphosphate / metabolism
  • Humans
  • Models, Molecular
  • Mutation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • Substrate Specificity
  • ras Proteins / chemistry
  • ras Proteins / metabolism


  • GTP-Binding Protein alpha Subunits
  • Receptors, G-Protein-Coupled
  • Guanosine Diphosphate
  • ras Proteins