ArticleNature chemical biology2023
Structural basis of efficacy-driven ligand selectivity at GPCRs.
Article in Nature chemical biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 25 papers.
What it found
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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.
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Who cites it
25 citing papers in PubMed.
- Atomic, structural and molecular insights into GPCR ligand binding and signalling.Nature reviews. Molecular cell biology · 2026Review
- BIENs: biomimetic interface encoding on FeMikrochimica acta · 2026Article
- Novel drug treatments for schizophrenia.Nature reviews. Drug discovery · 2026Review
- Dynamic-GLEP: a dynamics-informed deep learning framework for ligand efficacy prediction in representative Class A GPCRs.Briefings in bioinformatics · 2026Article
- DeepTargetClass: a web-based platform for predicting protein target classes of small molecules.Journal of computer-aided molecular design · 2025Article
- Targeting disrupted networks in schizophrenia: Can muscarinic drugs make a fundamental difference?Journal of psychopharmacology (Oxford, England) · 2025Review
- Advances in uncovering the mechanisms of macromolecular conformational entropy.Nature chemical biology · 2025Review
- CXC Chemokine Ligand 12 Facilitates Gi Protein Binding to CXC Chemokine Receptor 4 by Stabilizing Packing of the Proline-Isoleucine-Phenylalanine Motif: Insights from Automated Path Searching.Journal of the American Chemical Society · 2025Article
- Structure-guided design of partial agonists at an opioid receptor.Nature communications · 2025Article
- Structural basis of THC analog activity at the Cannabinoid 1 receptor.Nature communications · 2025Article
- A non-canonical mechanism of GPCR activation.Nature communications · 2024Article
- The Art and Science of Molecular Docking.Annual review of biochemistry · 2024Review
- Entropy drives the ligand recognition in G-protein-coupled receptor subtypes.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Structure-Guided Design of Partial Agonists at an Opioid Receptor.Research square · 2024Article
- A small-molecule activation mechanism that directly opens the KCNQ2 channel.Nature chemical biology · 2024Article
- Structural basis of ΔResearch square · 2024Article
- Guided diffusion for molecular generation with interaction prompt.Briefings in bioinformatics · 2024Article
- Fine-tuning activation specificity of G-protein-coupled receptors via automated path searching.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- GPCR-IPL score: multilevel featurization of GPCR-ligand interaction patterns and prediction of ligand functions from selectivity to biased activation.Briefings in bioinformatics · 2024Article
- Advances in ligand-specific biosensing for structurally similar molecules.Cell systems · 2023Review
Corrections and comments
- Erratum issued
Authors and funding
13 authors.
Funding
Abstract
A drug's selectivity for target receptors is essential to its therapeutic utility, but achieving selectivity between similar receptors is challenging. The serendipitous discovery of ligands that stimulate target receptors more strongly than closely related receptors, despite binding with similar affinities, suggests a solution. The molecular mechanism of such 'efficacy-driven selectivity' has remained unclear, however, hindering design of such ligands. Here, using atomic-level simulations, we reveal the structural basis for the efficacy-driven selectivity of a long-studied clinical drug candidate, xanomeline, between closely related muscarinic acetylcholine receptors (mAChRs). Xanomeline's binding mode is similar across mAChRs in their inactive states but differs between mAChRs in their active states, with divergent effects on active-state stability. We validate this mechanism experimentally and use it to design ligands with altered efficacy-driven selectivity. Our results suggest strategies for the rational design of ligands that achieve efficacy-driven selectivity for many pharmaceutically important G-protein-coupled receptors.
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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.