Development of an antibody fragment that stabilizes GPCR/G-protein complexes

Shoji Maeda, Antoine Koehl, Hugues Matile, Hongli Hu, Daniel Hilger, Gebhard F. X. Schertler, Aashish Manglik, Georgios Skiniotis, Roger J. P. Dawson () and Brian K. Kobilka ()
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Shoji Maeda: Stanford University School of Medicine
Antoine Koehl: Stanford University School of Medicine
Hugues Matile: F.Hoffmann-La Roche Ltd
Hongli Hu: Stanford University School of Medicine
Daniel Hilger: Stanford University School of Medicine
Gebhard F. X. Schertler: Paul Scherrer Institute
Aashish Manglik: University of California San Francisco
Georgios Skiniotis: Stanford University School of Medicine
Roger J. P. Dawson: F.Hoffmann-La Roche Ltd
Brian K. Kobilka: Stanford University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract Single-particle cryo-electron microscopy (cryo-EM) has recently enabled high-resolution structure determination of numerous biological macromolecular complexes. Despite this progress, the application of high-resolution cryo-EM to G protein coupled receptors (GPCRs) in complex with heterotrimeric G proteins remains challenging, owning to both the relative small size and the limited stability of these assemblies. Here we describe the development of antibody fragments that bind and stabilize GPCR-G protein complexes for the application of high-resolution cryo-EM. One antibody in particular, mAb16, stabilizes GPCR/G-protein complexes by recognizing an interface between Gα and Gβγ subunits in the heterotrimer, and confers resistance to GTPγS-triggered dissociation. The unique recognition mode of this antibody makes it possible to transfer its binding and stabilizing effect to other G-protein subtypes through minimal protein engineering. This antibody fragment is thus a broadly applicable tool for structural studies of GPCR/G-protein complexes.

Date: 2018
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DOI: 10.1038/s41467-018-06002-w

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