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

Author

Listed:
  • 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
    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
    University of California San Francisco)

  • Georgios Skiniotis

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Roger J. P. Dawson

    (F.Hoffmann-La Roche Ltd)

  • Brian K. Kobilka

    (Stanford University School of Medicine)

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.

Suggested Citation

  • Shoji Maeda & Antoine Koehl & Hugues Matile & Hongli Hu & Daniel Hilger & Gebhard F. X. Schertler & Aashish Manglik & Georgios Skiniotis & Roger J. P. Dawson & Brian K. Kobilka, 2018. "Development of an antibody fragment that stabilizes GPCR/G-protein complexes," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06002-w
    DOI: 10.1038/s41467-018-06002-w
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