ArticleNature2016
Activation of the A2A adenosine G-protein-coupled receptor by conformational selection.
Article in Nature, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 196 papers.
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Who cites it
196 citing papers in PubMed, 362 citations in OpenAlex.
- Deciphering the allosteric landscape of 5-HTPharmacological reports : PR · 2026Article
- An Excelled Trifluorinated Probe for GPCR Conformational Quantification.bioRxiv : the preprint server for biology · 2026Article
- New paradigm of q-CAR drug development targeting disease-specific protein conformations.npj drug discovery · 2026Review
- An Improved Cysteine-Based Labeling Strategy for GPCR Structural Dynamics Studies.Chemistry (Weinheim an der Bergstrasse, Germany) · 2026Article
- Kinetic model of partial agonism reveals cellular basis of ligand efficacy.The Journal of biological chemistry · 2026Article
- Activation dynamics of a water-soluble human mu-opioid receptor.The Journal of biological chemistry · 2026Article
- Molecular basis of CXC chemokine receptor 3 ligand multispecificity.Science advances · 2026Article
- Unraveling allosteric signaling of G protein-coupled receptors (GPCRs) by single-molecule fluorescence.Biophysical reviews · 2026Review
- Detection of an Antagonist Bound to the Neurokinin a Receptor in Styrene-Maleic Acid Lipid Particles byChembiochem : a European journal of chemical biology · 2026Article
- The role of the tryptophan-rich allosteric network and sodium egress in GPCR activation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- ABEL-FRET bridges the timescale gap in single-molecule measurements of the structural dynamics in the ACommunications chemistry · 2026Article
- Article
- The Role of Intrinsically Disordered Domains in Regulating G Protein-Coupled Receptor Signaling.Journal of the American Chemical Society · 2026Article
- The Allosteric Mechanism of G-Protein-Coupled Receptors is Induced Fit, Not Conformational Selection.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Conformational Heterogeneity Underlying Divergent Signaling in Class A G Protein-Coupled Receptors.ACS pharmacology & translational science · 2025Review
- TRPM8 Protein Dynamics Correlates with Ligand Structure and Cellular Function.Journal of the American Chemical Society · 2025Article
- The Conformational Equilibria of a Human GPCR Compared between Lipid Vesicles and Aqueous Solutions by IntegrativeJournal of the American Chemical Society · 2025Article
- TRPM8 protein dynamics correlates with ligand structure and cellular function.bioRxiv : the preprint server for biology · 2025Article
- Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery.Nature reviews. Drug discovery · 2025Review
- Investigation of structural and dynamic properties of the Butyrophilin BTN3A1/BTN2A1 cytoplasmic complex byFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
136 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Conformational selection and induced fit are two prevailing mechanisms to explain the molecular basis for ligand-based activation of receptors. G-protein-coupled receptors are the largest class of cell surface receptors and are important drug targets. A molecular understanding of their activation mechanism is critical for drug discovery and design. However, direct evidence that addresses how agonist binding leads to the formation of an active receptor state is scarce. Here we use (19)F nuclear magnetic resonance to quantify the conformational landscape occupied by the adenosine A2A receptor (A2AR), a prototypical class A G-protein-coupled receptor. We find an ensemble of four states in equilibrium: (1) two inactive states in millisecond exchange, consistent with a formed (state S1) and a broken (state S2) salt bridge (known as 'ionic lock') between transmembrane helices 3 and 6; and (2) two active states, S3 and S3', as identified by binding of a G-protein-derived peptide. In contrast to a recent study of the β2-adrenergic receptor, the present approach allowed identification of a second active state for A2AR. Addition of inverse agonist (ZM241385) increases the population of the inactive states, while full agonists (UK432097 or NECA) stabilize the active state, S3', in a manner consistent with conformational selection. In contrast, partial agonist (LUF5834) and an allosteric modulator (HMA) exclusively increase the population of the S3 state. Thus, partial agonism is achieved here by conformational selection of a distinct active state which we predict will have compromised coupling to the G protein. Direct observation of the conformational equilibria of ligand-dependent G-protein-coupled receptor and deduction of the underlying mechanisms of receptor activation will have wide-reaching implications for our understanding of the function of G-protein-coupled receptor in health and disease.
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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.