Structural Insights into the Process of GPCR-G Protein Complex Formation

Cell. 2019 May 16;177(5):1243-1251.e12. doi: 10.1016/j.cell.2019.04.021. Epub 2019 May 9.


The crystal structure of the β2-adrenergic receptor (β2AR) bound to the G protein adenylyl cyclase stimulatory G protein (Gs) captured the complex in a nucleotide-free state (β2AR-Gsempty). Unfortunately, the β2AR-Gsempty complex does not provide a clear explanation for G protein coupling specificity. Evidence from several sources suggests the existence of a transient complex between the β2AR and GDP-bound Gs protein (β2AR-GsGDP) that may represent an intermediate on the way to the formation of β2AR-Gsempty and may contribute to coupling specificity. Here we present a structure of the β2AR in complex with the carboxyl terminal 14 amino acids from Gαs along with the structure of the GDP-bound Gs heterotrimer. These structures provide evidence for an alternate interaction between the β2AR and Gs that may represent an intermediate that contributes to Gs coupling specificity.

Keywords: G protein; G protein-coupled receptor; coupling specificity; intermediate state; protein engineering.

Publication types

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

MeSH terms

  • Adenylyl Cyclases / chemistry*
  • GTP-Binding Protein alpha Subunits, Gs / chemistry*
  • Humans
  • Models, Molecular*
  • Receptors, Adrenergic, beta-2 / chemistry*
  • Structure-Activity Relationship


  • Receptors, Adrenergic, beta-2
  • GTP-Binding Protein alpha Subunits, Gs
  • Adenylyl Cyclases