Cannabinoid receptor-G protein interactions: G(alphai1)-bound structures of IC3 and a mutant with altered G protein specificity

Protein Sci. 2002 Oct;11(10):2526-31. doi: 10.1110/ps.0218402.


The structure of the C-terminal region of the third cytoplasmic loop (IC3) of the cannabinoid receptor one (CB1) bound to G(alphai1) has been determined using transferred nuclear Overhauser effects (NOEs). The wild-type IC3 sequence is helical when associated with G(alphai1). In contrast, a peptide containing the amino-acid inversion, Ala(341)-Leu(342) adopts a single turn. These findings correlate with the attenuated G(i) association of CB1 with the Ala(341)-Leu(342) mutation previously observed in vivo and the diminished stimulation of G(alphai1) GTPase activity by the corresponding peptide demonstrated in vitro here. These results, the first to report the structure of a GPCR domain while associated with G protein, imply the C-terminus of CB1 IC3, a region with high-sequence conservation among G-protein coupled receptors, must be helical for efficient coupling and activation of the G(i) protein.

MeSH terms

  • GTP-Binding Proteins / metabolism*
  • Mutation
  • Protein Binding / genetics*
  • Protein Structure, Tertiary
  • Receptors, Cannabinoid
  • Receptors, Drug / genetics
  • Receptors, Drug / metabolism*
  • Structure-Activity Relationship


  • Receptors, Cannabinoid
  • Receptors, Drug
  • GTP-Binding Proteins