Elucidating biased signaling in class A GPCRs. Trends Pharmacol Sci 2025 Dec;46(12):1190-1208
Date
11/09/2025Pubmed ID
41206221Pubmed Central ID
PMC12991348DOI
10.1016/j.tips.2025.10.008Scopus ID
2-s2.0-105021050734 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
Biased signaling by G protein-coupled receptors (GPCRs) occurs when ligands selectively activate G proteins or β-arrestins, offering therapeutic potential with fewer side effects. In class A GPCRs, which include the targets of approximately one-third of all marketed drugs, the structural basis of this selectivity remains unclear. Recent cryo-electron microscopy studies, supported by real-time functional assays such as bioluminescence resonance energy transfer and NanoLuc Binary Technology, reveal how distinct ligand binding modes reshape receptor conformations to favor specific transducer engagement. Integrating structural and functional insights enables mapping of isoform- and tissue-specific signaling. Here, we review key mechanisms of bias, including microswitch transitions, intracellular interface remodeling, and allosteric modulation, and provide a mechanistic basis for pathway-selective GPCR-targeting therapeutics with improved efficacy and reduced off-target effects.
Author List
Xu N, Legall E, Johnson RH, Zhu L, Liu WAuthors
Roger H. Johnson PhD, BA Associate Professor in the Biophysics department at Medical College of WisconsinWei Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsHumans
Ligands
Receptors, G-Protein-Coupled
Signal Transduction
