ArticleThe Journal of biological chemistry2014
Divergent transducer-specific molecular efficacies generate biased agonism at a G protein-coupled receptor (GPCR).
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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Who cites it
87 citing papers in PubMed.
- Molecular Determinants of G Protein Subtype-Specific Coupling to the Angiotensin II Type 1 Receptor.bioRxiv : the preprint server for biology · 2026Article
- Activation of the angiotensin II type I receptor by a nonpeptide agonist.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- β-arrestin recruitment facilitates a direct association with G proteins.Nature communications · 2026Article
- Conformational Basis of Functionally Selective Allosteric Modulation of the Angiotensin II type 1 Receptor by Small Molecules.bioRxiv : the preprint server for biology · 2026Article
- Mechanism of beta-arrestin 1 mediated Src activation via Src SH3 domain revealed by cryo-electron microscopy.Nature communications · 2026Article
- Galanin Receptors: G Protein-Dependent Signaling and Beyond.Biomolecules · 2026Review
- The ABCs of psychedelics: a preclinical roadmap for drug discovery.Trends in pharmacological sciences · 2025Review
- Biased Agonists of the Type 1 Angiotensin II Receptor Promote Distinct Subcellular β-Arrestin Conformations.Biochemistry · 2025Article
- Mechanism of beta-arrestin 1 mediated Src activation via Src SH3 domain revealed by cryo-electron microscopy.bioRxiv : the preprint server for biology · 2025Article
- Structural insights into GPCR signaling activated by peptide ligands: from molecular mechanism to therapeutic application.Experimental & molecular medicine · 2025Review
- S1PR1-biased activation drives the resolution of endothelial dysfunction-associated inflammatory diseases by maintaining endothelial integrity.Nature communications · 2025Article
- Positive allosteric modulation of a GPCR ternary complex.Science advances · 2024Article
- Phosphorylation patterns in the AT1R C-terminal tail specify distinct downstream signaling pathways.Science signaling · 2024Article
- Nanobody-Mediated Dualsteric Engagement of the Angiotensin Receptor Broadens Biased Ligand Pharmacology.Molecular pharmacology · 2024Article
- Information Transmission in G Protein-Coupled Receptors.International journal of molecular sciences · 2024Review
- Single-Molecule Imaging Reveals Differential AT1R Stoichiometry Change in Biased Signaling.International journal of molecular sciences · 2023Article
- Article
- Quantitative assessment of ligand bias from bias plots: The bias coefficient "kappa".Biochimica et biophysica acta. General subjects · 2023Article
- Allosteric modulator potentiates β2AR agonist-promoted bronchoprotection in asthma models.The Journal of clinical investigation · 2023Article
- Angiotensin ATCell reports · 2023Article
27 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors.
Funding
Abstract
The concept of "biased agonism" arises from the recognition that the ability of an agonist to induce a receptor-mediated response (i.e. "efficacy") can differ across the multiple signal transduction pathways (e.g. G protein and β-arrestin (βarr)) emanating from a single GPCR. Despite the therapeutic promise of biased agonism, the molecular mechanism(s) whereby biased agonists selectively engage signaling pathways remain elusive. This is due in large part to the challenges associated with quantifying ligand efficacy in cells. To address this, we developed a cell-free approach to directly quantify the transducer-specific molecular efficacies of balanced and biased ligands for the angiotensin II type 1 receptor (AT1R), a prototypic GPCR. Specifically, we defined efficacy in allosteric terms, equating shifts in ligand affinity (i.e. KLo/KHi) at AT1R-Gq and AT1R-βarr2 fusion proteins with their respective molecular efficacies for activating Gq and βarr2. Consistent with ternary complex model predictions, transducer-specific molecular efficacies were strongly correlated with cellular efficacies for activating Gq and βarr2. Subsequent comparisons across transducers revealed that biased AT1R agonists possess biased molecular efficacies that were in strong agreement with the signaling bias observed in cellular assays. These findings not only represent the first measurements of the thermodynamic driving forces underlying differences in ligand efficacy between transducers but also support a molecular mechanism whereby divergent transducer-specific molecular efficacies generate biased agonism at a GPCR.
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