Structure of the adenosine-bound human adenosine A 1 receptor-G i complex

Nature. 2018 Jun;558(7711):559-563. doi: 10.1038/s41586-018-0236-6. Epub 2018 Jun 20.

Abstract

The class A adenosine A1 receptor (A1R) is a G-protein-coupled receptor that preferentially couples to inhibitory Gi/o heterotrimeric G proteins, has been implicated in numerous diseases, yet remains poorly targeted. Here we report the 3.6 Å structure of the human A1R in complex with adenosine and heterotrimeric Gi2 protein determined by Volta phase plate cryo-electron microscopy. Compared to inactive A1R, there is contraction at the extracellular surface in the orthosteric binding site mediated via movement of transmembrane domains 1 and 2. At the intracellular surface, the G protein engages the A1R primarily via amino acids in the C terminus of the Gαi α5-helix, concomitant with a 10.5 Å outward movement of the A1R transmembrane domain 6. Comparison with the agonist-bound β2 adrenergic receptor-Gs-protein complex reveals distinct orientations for each G-protein subtype upon engagement with its receptor. This active A1R structure provides molecular insights into receptor and G-protein selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / chemistry*
  • Adenosine / metabolism*
  • Binding Sites
  • Cryoelectron Microscopy*
  • GTP-Binding Protein alpha Subunits, Gi-Go / chemistry*
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • GTP-Binding Protein alpha Subunits, Gi-Go / ultrastructure*
  • GTP-Binding Protein alpha Subunits, Gs / chemistry
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • Humans
  • Models, Molecular
  • Receptor, Adenosine A1 / chemistry*
  • Receptor, Adenosine A1 / metabolism
  • Receptor, Adenosine A1 / ultrastructure*
  • Rotation
  • Substrate Specificity

Substances

  • Receptor, Adenosine A1
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • GTP-Binding Protein alpha Subunits, Gs
  • Adenosine