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Annual Review of Pharmacology and Toxicology

Volume 65, 2025

GPCR Biosensors to Study Conformational Dynamics and Signaling in Drug Discovery

  • Victoria R. Saca1,2, Colin Burdette1,2 and Thomas P. Sakmar1
  • 1Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, NY, USA; email: [email protected] 2Tri-Institutional PhD Program in Chemical Biology, New York, NY, USA
  • Vol. 65:7-28 (Volume publication date January 2025)
  • First published as a Review in Advance on September 19, 2024
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

G protein–coupled receptors (GPCRs) are a superfamily of transmembrane signal transducers that facilitate the flow of chemical signals across membranes. GPCRs are a desirable class of drug targets, and the activation and deactivation dynamics of these receptors are widely studied. Multidisciplinary approaches for studying GPCRs, such as downstream biochemical signaling assays, cryo-electron microscopy structural determinations, and molecular dynamics simulations, have provided insights concerning conformational dynamics and signaling mechanisms. However, new approaches including biosensors that use luminescence- and fluorescence-based readouts have been developed to investigate GPCR-related protein interactions and dynamics directly in cellular environments. Luminescence- and fluorescence-based readout approaches have also included the development of GPCR biosensor platforms that utilize enabling technologies to facilitate multiplexing and miniaturization. General principles underlying the biosensor platforms and technologies include scalability, orthogonality, and kinetic resolution. Further application and development of GPCR biosensors could facilitate hit identification in drug discovery campaigns. The goals of this review are to summarize developments in the field of GPCR-related biosensors and to discuss the current available technologies.

Keyword(s): biosensor, drug discovery, G protein–coupled receptor, GPCR, protein-protein interactions, resonance energy transfer, RET
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2025-01-23
2025-06-15
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/content/journals/10.1146/annurev-pharmtox-061724-080836
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GPCR Biosensors to Study Conformational Dynamics and Signaling in Drug Discovery
Annual Review of Pharmacology and Toxicology 65, 7 (2025); https://doi.org/10.1146/annurev-pharmtox-061724-080836
/content/journals/10.1146/annurev-pharmtox-061724-080836
/content/journals/10.1146/annurev-pharmtox-061724-080836
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