ArticleNature communications2024
A non-canonical mechanism of GPCR activation.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Deciphering the allosteric landscape of 5-HTPharmacological reports : PR · 2026Article
- Lipid Activation of a Thalamic GPCR Extends Working Memory Time-scales.bioRxiv : the preprint server for biology · 2026Article
- Sequence constraints predispose Class D GPCRs to follow an atypical activation mechanism.bioRxiv : the preprint server for biology · 2026Article
- The Role of Intrinsically Disordered Domains in Regulating G Protein-Coupled Receptor Signaling.Journal of the American Chemical Society · 2026Article
- All roads lead to Rome: Emergence of Mechanistic Divergence Shapes Activation of Class B1 G-Protein Coupled Receptors.bioRxiv : the preprint server for biology · 2026Article
- Systematic metabolite screening identifies functional regulators of the adenosine A2A receptor.Communications chemistry · 2025Article
- Temporally resolved and interpretable machine learning model of GPCR conformational transition.Nature communications · 2025Article
- Exploring the distinct activation mechanisms of neuromedin B receptor through multiple replica molecular dynamics simulations and Markov state modeling.Acta pharmacologica Sinica · 2025Article
- Bitopic AJournal of medicinal chemistry · 2025Article
- The role of intrinsically disordered domains in regulating G protein coupled receptor signaling.bioRxiv : the preprint server for biology · 2025Article
- Distinct Phosphorylation Patterns of AT1R by Biased Ligands and GRK Subtypes.International journal of molecular sciences · 2025Article
- Cryo-EM reveals an extrahelical allosteric binding site at the MNature communications · 2025Article
- Article
- Identification of a Lipid-Exposed Extrahelical Binding Site for Positive Allosteric Modulators of the Dopamine DACS chemical neuroscience · 2025Article
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11 authors.
Funding
Abstract
The goal of designing safer, more effective drugs has led to tremendous interest in molecular mechanisms through which ligands can precisely manipulate the signaling of G-protein-coupled receptors (GPCRs), the largest class of drug targets. Decades of research have led to the widely accepted view that all agonists-ligands that trigger GPCR activation-function by causing rearrangement of the GPCR's transmembrane helices, opening an intracellular pocket for binding of transducer proteins. Here we demonstrate that certain agonists instead trigger activation of free fatty acid receptor 1 by directly rearranging an intracellular loop that interacts with transducers. We validate the predictions of our atomic-level simulations by targeted mutagenesis; specific mutations that disrupt interactions with the intracellular loop convert these agonists into inverse agonists. Further analysis suggests that allosteric ligands could regulate the signaling of many other GPCRs via a similar mechanism, offering rich possibilities for precise control of pharmaceutically important targets.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.