G protein-coupled receptors (GPCRs) adopt multiple conformational states that can activate or block distinct intracellular signalling pathways, such as those regulated by heterotrimeric G proteins or β-arrestins.
Different agonists for the same receptor can stabilize distinct GPCR conformational states. Agonists that preferentially activate certain intracellular pathways relative to others are referred to as biased agonists.
Structural studies support a model in which GPCRs act as allosteric microprocessors that integrate diverse extracellular and intracellular stimuli to generate distinct conformations that result in varied intracellular responses.
In addition to biased agonists, biased signalling may be encoded by the receptor ('receptor bias') or by the relative expression levels of transducers ('system bias').
Biased signalling is also observed in other receptor families, such as nuclear hormone receptors and receptor tyrosine kinases.
Recent preclinical and clinical work suggests that by more selectively targeting signalling pathways of interest, biased agonists have the potential to increase clinical efficacy while reducing undesirable side effects.
G protein-coupled receptors (GPCRs) are the largest class of receptors in the human genome and some of the most common drug targets. It is now well established that GPCRs can signal through multiple transducers, including heterotrimeric G proteins, GPCR kinases and β-arrestins. While these signalling pathways can be activated or blocked by 'balanced' agonists or antagonists, they can also be selectively activated in a 'biased' response. Biased responses can be induced by biased ligands, biased receptors or system bias, any of which can result in preferential signalling through G proteins or β-arrestins. At many GPCRs, signalling events mediated by G proteins and β-arrestins have been shown to have distinct biochemical and physiological actions from one another, and an accurate evaluation of biased signalling from pharmacology through physiology is crucial for preclinical drug development. Recent structural studies have provided snapshots of GPCR–transducer complexes, which should aid in the structure-based design of novel biased therapies. Our understanding of GPCRs has evolved from that of two-state, on-and-off switches to that of multistate allosteric microprocessors, in which biased ligands transmit distinct structural information that is processed into distinct biological outputs. The development of biased ligands as therapeutics heralds an era of increased drug efficacy with reduced drug side effects.
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The authors thank J. Silverman for helpful discussion on error propagation and for design and implementation of the online biased calculator resource. We thank T. Pack, M. Caron and C. Chavkin for comments on sections of the manuscript. This work is supported by NIH Grants T32GM7171 (J.S.S.), HL16037 (R.J.L.), HL114643 (S.R.) and GM122798 (S.R.); the Duke Medical Scientist Training Program (J.S.S.); a Burroughs Wellcome Career Award for Medical Scientists (S.R.). R.J.L. is an HHMI Investigator.
R.J.L. is a co-founder and shareholder of Trevena.
- G protein-coupled receptor kinases
(GRKs). A family of serine/threonine kinases that phosphorylate the intracellular residues of a G protein-coupled receptor following agonist binding, which is often required for β-arrestin recruitment and signalling.
Multifunctional adaptor proteins that regulate G protein-coupled receptor (GPCR) signalling through desensitization and internalization and by promoting signalling through a wide variety of pathways. They also regulate non-GPCR targets, such as receptor tyrosine kinases.
The ability of a ligand to generate a quantifiable response after binding to a receptor.
A measurement of how well a ligand binds to a receptor, commonly expressed in terms of a dissociation constant (Kd). Affinity depends on cellular context, and therefore affinity for a G protein-coupled receptor is influenced by transducers, such as G proteins and β-arrestins.
- Ligand bias
Biased signalling encoded in the ligand that generates a distinct ligand–receptor conformation relative to a reference ligand.
- Allosteric modulators
Ligands that bind to an allosteric site of the receptor and affect receptor responses to orthosteric ligands. Some allosteric modulators are capable of generating biased responses.
- Biased agonists
Ligands that selectively enhance or attenuate some, but not all, of the signalling pathways available to a receptor compared with a reference ligand (usually an endogenous agonist).
- Receptor bias
Biased signalling encoded by differences in receptor structure or conformation compared with the 'wild-type' receptor.
- System bias
Biased signalling directed by the relative expression of receptor transducers, such as increased expression of G proteins, G protein-coupled receptor kinases and/or β-arrestins.
- Orthosteric site
The site on a receptor to which the endogenous ligand binds.
- Allosteric site
A binding site on a receptor that is different from the orthosteric site.
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Smith, J., Lefkowitz, R. & Rajagopal, S. Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov 17, 243–260 (2018). https://doi.org/10.1038/nrd.2017.229
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