G protein-coupled receptors (GPCRs) are the largest group of cell surface receptors in humans that signal in response to diverse inputs and regulate a plethora of cellular processes. Hence, they constitute one of the primary drug target classes. Progress in our understanding of GPCR dynamics, activation and signalling has opened new possibilities for selective drug development. A key advancement has been provided by the concept of biased agonism, which describes the ability of ligands acting at the same GPCR to elicit distinct cellular signalling profiles by preferentially stabilizing different active conformational states of the receptor. Application of this concept raises the prospect of ‘designer’ biased agonists as optimized therapeutics with improved efficacy and/or reduced side-effect profiles. However, this application will require a detailed understanding of the spectrum of drug actions and a structural understanding of the drug–receptor interactions that drive distinct pharmacologies. The recent revolution in GPCR structural biology provides unprecedented insights into ligand binding, conformational dynamics and the control of signalling outcomes. These insights, together with new approaches to multi-dimensional analysis of drug action, are allowing refined classification of drugs according to their pharmacodynamic profiles, which can be linked to receptor structure and predictions of preclinical drug efficacy.
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Common Gα Subunit Numbering (CGN): https://www.mrc-lmb.cam.ac.uk/CGN/GPCR Drug Browser: http://gpcrdb.org/drugs/drugbrowserGPCR Database: www.gpcrdb.orgNatural variation of GPCRs in the human population: http://www.gpcrdb.org/mutational_landscape/statisticsProtein Contacts Atlas: https://www.mrc-lmb.cam.ac.uk/pcaSelectivity determinants of GPCR–G protein signalling: http://www.gpcrdb.org/signprot/statistics
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P.M.S., A.C. and D.W. are Principal, Senior Principal and Career Development Fellows of the National Health and Medical Research Council of Australia, respectively. M.M.B. and M.M.-S. acknowledge the UK Medical Research Council (MC_U105185859) for support. M.M.-S. is supported by a Federation of European Biochemical Societies Long-Term Fellowship, and M.M.B. is a Lister Institute Fellow and is also supported by the European Research Council (ERC-COG-2015-682414).
Nature Reviews Molecular Cell Biology thanks T. Hebert, V. Katritch, S. Rajagopal and the other anonymous reviewer(s) for their contribution to the peer review of this work.
A light-sensitive G protein-coupled receptor involved in visual phototransduction.
A family of intracellular transducers that can act as G protein-coupled receptor modulators by blocking G protein-mediated signalling, promoting receptor internalization and activating G protein-independent signalling pathways.
A molecule that binds to and stabilizes the receptor in an active conformation, thereby resulting in an intracellular response.
- Bioluminescence resonance energy transfer
(BRET). A biophysical technique combining a photon-emitting bioluminescent luciferase and an acceptor fluorescent protein, which is used to monitor changes in intramolecular and intermolecular proximity.
- Fluorescence resonance energy transfer
(FRET). A biophysical technique combining a donor chromophore and an acceptor chromophore, which is used to monitor changes in intramolecular and intermolecular proximity.
- GPCR kinases
(GRKs). G protein-coupled receptor (GPCR)-regulating protein kinases that phosphorylate intracellular receptor sites and modulate the ability of GPCRs to interact with G proteins and other intracellular transducers.
- Transducer mimetic
A non-functional protein such as a camelid nanobody that binds within the transducer-binding cleft of an activated receptor to induce structural reorganization of the receptor similar to that induced by functional transducers (for example, G proteins).
- Inhibitory antibody
An antibody directed against a G protein-coupled receptor that inhibits receptor activation.
- Protein signalosome
A spatially restricted group of transducers and/or regulatory proteins that jointly produce a specific signalling output.
A chemical description of a molecule that allows identification of the similarities and differences in chemical structure compared with other molecules.
- Chemogenetically modified receptors
Genetically engineered receptors that can be chemically modified to be able to alter receptor signalling properties. These include receptors selected for their capacity to interact with previously unrecognized ligands.
A biophysical technique that uses modified, light-activated G protein-coupled receptors or channels to control cells in living tissue.
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