Structural basis and mechanism of activation of two different families of G proteins by the same GPCR

Nat Struct Mol Biol. 2021 Nov;28(11):936-944. doi: 10.1038/s41594-021-00679-2. Epub 2021 Nov 10.


The β1-adrenergic receptor (β1-AR) can activate two families of G proteins. When coupled to Gs, β1-AR increases cardiac output, and coupling to Gi leads to decreased responsiveness in myocardial infarction. By comparative structural analysis of turkey β1-AR complexed with either Gi or Gs, we investigate how a single G-protein-coupled receptor simultaneously signals through two G proteins. We find that, although the critical receptor-interacting C-terminal α5-helices on Gαi and Gαs interact similarly with β1-AR, the overall interacting modes between β1-AR and G proteins vary substantially. Functional studies reveal the importance of the differing interactions and provide evidence that the activation efficacy of G proteins by β1-AR is determined by the entire three-dimensional interaction surface, including intracellular loops 2 and 4 (ICL2 and ICL4).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiac Output / genetics
  • Cardiac Output / physiology
  • Cell Line
  • Cryoelectron Microscopy
  • Cyclic AMP / metabolism
  • Enzyme Activation / physiology
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • GTP-Binding Protein alpha Subunits, Gs / metabolism*
  • HEK293 Cells
  • Heart Diseases / pathology
  • Humans
  • Hypertension / pathology
  • Isoproterenol / chemistry
  • Protein Structure, Secondary / physiology
  • Protein Structure, Tertiary / physiology*
  • Receptors, Adrenergic, beta-1 / metabolism*
  • Sf9 Cells
  • Signal Transduction / physiology


  • ADRB1 protein, human
  • Receptors, Adrenergic, beta-1
  • Cyclic AMP
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • GTP-Binding Protein alpha Subunits, Gs
  • Isoproterenol