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


Meng Zhang, Miao Gui, Zi-Fu Wang, Christoph Gorgulla, James J. Yu, Hao Wu, Zhen-yu J. Sun, Christoph Klenk, Lisa Merklinger, Lena Morstein, Franz Hagn, Andreas Plückthun, Alan Brown, Mahmoud L. Nasr, and Gerhard Wagner. 2021. “Cryo-EM structure of an activated GPCR–G protein complex in lipid nanodiscs.” Nature Structural & Molecular Biology, 28, 3, Pp. 258-267. Publisher's Version


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 4.2þinspace}\AA. 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.
Last updated on 03/11/2021