Cryo-EM structure of an activated GPCR-G protein complex in lipid nanodiscs

Structures of GPCR neurotensin receptor 1 (NTSR1) in complex with neurotensin and G alpha(i1)beta(1)gamma(1) in a lipid bilayer environment and without stabilizing antibodies reveal extensive interactions at the GPCR-G protein interface. G-protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane proteins and the targets of over 30% of currently marketed pharmaceuticals. Although several structures have been solved for GPCR-G protein complexes, few are in a lipid membrane environment. Here, we report cryo-EM structures of complexes of neurotensin, neurotensin receptor 1 and G alpha(i1)beta(1)gamma(1) in two conformational states, resolved to resolutions of 4.1 and 4.2 angstrom. The structures, determined in a lipid bilayer without any stabilizing antibodies or nanobodies, reveal an extended network of protein-protein interactions at the GPCR-G protein interface as compared to structures obtained in detergent micelles. The findings show that the lipid membrane modulates the structure and dynamics of complex formation and provide a molecular explanation for the stronger interaction between GPCRs and G proteins in lipid bilayers. We propose an allosteric mechanism for GDP release, providing new insights into the activation of G proteins for downstream signaling.

Automated summary

Recent studies have uncovered the complex interactions between neurotensin receptor 1, neurotensin, and G proteins in a lipid bilayer environment, revealing a more intricate network of protein-protein interactions compared to structures obtained in detergent micelles. These findings provide new insights into the modulation of complex formation by lipid membranes and propose an allosteric mechanism for GDP release in G protein activation.