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Zhang, M.* ; Gui, M.* ; Wang, Z.F.* ; Gorgulla, C.* ; Yu, J.J.* ; Wu, H.* ; Sun, Z.J.* ; Klenk, C.* ; Merklinger, L.* ; Morstein, L.* ; Hagn, F. ; Plückthun, A.* ; Brown, A.* ; Nasr, M.L.* ; Wagner, G.*

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

Nat. Struct. Mol. Biol. 28, 258-267 (2021)

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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 Gα_i1β₁γ₁ in two conformational states, resolved to resolutions of 4.1 and 4.2 Å. 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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

ISSN (print) / ISBN 1545-9993

e-ISSN 1545-9985

Journal Nature Structural & Molecular Biology

Quellenangaben Volume: 28, Issue: 3, Pages: 258-267

Publisher Nature Publishing Group

Publishing Place New York, NY

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Structural Biology (STB)

Grants Swiss National Science Foundation
Merck-BCMP fellowship
International Retinal Research Foundation
E. Matilda Ziegler Foundation for the Blind
Richard and Susan Smith Family Foundation
Pew Charitable Trusts
NIH
HFSP
Charles Robert Broderick III Phytocannabinoid Research Fellowship