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G Protein-Coupled Receptors in Drug Discovery pp 67–77Cite as

Understanding the Ligand–Receptor–G Protein Ternary Complex for GPCR Drug Discovery

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 552))

Summary

Understanding the ternary complex between G protein-coupled receptors (GPCRs), cognate G proteins, and their ligands is an important landmark for drug discovery. Yet, little is known about the specific interactions between GPCRs and G proteins. For a better perspective on the ternary complex dynamics, we adapted a β2-adrenergic receptor(β2AR)–tetGsα reconstitution system and found evidence that for efficient coupling of the β2AR to Gs does not require specific interactions between the βγ-subunits and the β2AR. Our results demonstrate that specific interactions between βγ and the β2AR are not required for G protein activation but likely serve to anchor Gsα to the plasma membrane. Our results also suggests that the advantages of analysis of G protein activation by using β2AR receptor–tetGsα system in vitro at the close proximity of the receptor may constitute a simple screening system that avoids false positives and potentially adapted to screen drugs for other GPCRs.

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Acknowledgment

We thank Roger Sunahara for providing us with purified β1γ2-subunits of G proteins.

Author information

Authors and Affiliations

  1. Vertex Pharmaceuticals, Inc., Cambridge, MA, USA

    Venkata R.P. Ratnala

  2. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA

    Brian Kobilka

Authors
  1. Venkata R.P. Ratnala
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  2. Brian Kobilka
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Editors and Affiliations

  1. CSIRO Human Nutrition, Kintore Ave., Adelaide, 5000, Australia

    Wayne R. Leifert

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© 2009 Humana Press, a part of Springer Science+Business Media, LLC

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Ratnala, V.R., Kobilka, B. (2009). Understanding the Ligand–Receptor–G Protein Ternary Complex for GPCR Drug Discovery. In: Leifert, W. (eds) G Protein-Coupled Receptors in Drug Discovery. Methods in Molecular Biology, vol 552. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-317-6_5

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  • DOI: https://doi.org/10.1007/978-1-60327-317-6_5

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60327-316-9

  • Online ISBN: 978-1-60327-317-6

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