ArticleNature2013
Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs.
Article in Nature, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 187 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
187 citing papers in PubMed, 421 citations in OpenAlex.
- AlloPool is a deep learning framework that infers protein allostery from molecular dynamics simulations.PLoS biology · 2026Article
- Article
- Identification of Potential Bioactive Compounds in Strong-Flavor-Type Baijiu via Integration of Widely Targeted Metabolomics and Network Pharmacology.Foods (Basel, Switzerland) · 2026Article
- Nanobodies unlock new mechanisms to target G protein-coupled receptors.Molecular pharmacology · 2026Review
- A Transferable and Robust Computational Framework for Class A GPCR Activation Free Energies.The journal of physical chemistry letters · 2026Article
- Agonism and Biased Signaling.Handbook of experimental pharmacology · 2026Review
- Resistance to Allosteric Inhibitors.Journal of molecular biology · 2025Review
- Cryo-EM reveals an extrahelical allosteric binding site at the MNature communications · 2025Article
- Reaction Coordinates Are Optimal Channels of Energy Flow.Annual review of physical chemistry · 2025Review
- Enhanced sampling of protein conformational changes via true reaction coordinates from energy relaxation.Nature communications · 2025Article
- Systematic analysis of biomolecular conformational ensembles with PENSA.The Journal of chemical physics · 2025Article
- A non-canonical mechanism of GPCR activation.Nature communications · 2024Article
- MEF-AlloSite: an accurate and robust Multimodel Ensemble Feature selection for the Allosteric Site identification model.Journal of cheminformatics · 2024Article
- Positive allosteric modulation of a GPCR ternary complex.Science advances · 2024Article
- Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1.The journal of physical chemistry. B · 2024Article
- The value of protein allostery in rational anticancer drug design: an update.Expert opinion on drug discovery · 2024Review
- The Art and Science of Molecular Docking.Annual review of biochemistry · 2024Review
- The Inferential Binding Sites of GCGR for Small Molecules Using Protein Dynamic Conformations and Crystal Structures.International journal of molecular sciences · 2024Article
- Exploring Conformational Landscapes Along Anharmonic Low-Frequency Vibrations.The journal of physical chemistry. B · 2024Article
- Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode.Nature communications · 2024Review
127 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
14 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The design of G-protein-coupled receptor (GPCR) allosteric modulators, an active area of modern pharmaceutical research, has proved challenging because neither the binding modes nor the molecular mechanisms of such drugs are known. Here we determine binding sites, bound conformations and specific drug-receptor interactions for several allosteric modulators of the M2 muscarinic acetylcholine receptor (M2 receptor), a prototypical family A GPCR, using atomic-level simulations in which the modulators spontaneously associate with the receptor. Despite substantial structural diversity, all modulators form cation-π interactions with clusters of aromatic residues in the receptor extracellular vestibule, approximately 15 Å from the classical, 'orthosteric' ligand-binding site. We validate the observed modulator binding modes through radioligand binding experiments on receptor mutants designed, on the basis of our simulations, either to increase or to decrease modulator affinity. Simulations also revealed mechanisms that contribute to positive and negative allosteric modulation of classical ligand binding, including coupled conformational changes of the two binding sites and electrostatic interactions between ligands in these sites. These observations enabled the design of chemical modifications that substantially alter a modulator's allosteric effects. Our findings thus provide a structural basis for the rational design of allosteric modulators targeting muscarinic and possibly other GPCRs.
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What OpenQuestion holds
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.