ArticleNature communications2019
Cryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs.
Article in Nature communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 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
41 citing papers in PubMed, 74 citations in OpenAlex.
- CryptoBank: A resource for the identification and prediction of cryptic sites in proteins.Science advances · 2026Article
- AI-Driven Design of Miniproteins as Potential Allosteric Modulators.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Structure-based Discovery of a Non-competitive FTO Inhibitor Bound to a Cryptic Site at the Domain Interface.Journal of molecular biology · 2026Article
- Article
- Molecular basis of ligand binding and receptor activation at the human ANature communications · 2025Article
- Christian Bohr. Discoverer of Homotropic and Heterotopic Allostery: Periods Leading up to Bohr's Life, Work, and Beyond. Was Bohr a Vitalist and Right About a "Specific Activity"?Acta physiologica (Oxford, England) · 2025Review
- Role of artificial intelligence in revolutionizing drug discovery.Fundamental research · 2025Review
- Allostery and Evolution: A Molecular Journey Through the Structural and Dynamical Landscape of an Enzyme Super Family.Molecular biology and evolution · 2025Article
- Integrative residue-intuitive machine learning and MD Approach to Unveil Allosteric Site and Mechanism for β2AR.Nature communications · 2024Article
- Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies.Signal transduction and targeted therapy · 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
- A small-molecule activation mechanism that directly opens the KCNQ2 channel.Nature chemical biology · 2024Article
- Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode.Nature communications · 2024Review
- G protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery.Signal transduction and targeted therapy · 2024Review
- Analysing the effect caused by increasing the molecular volume in M1-AChR receptor agonists and antagonists: a structural and computational study.RSC advances · 2024Article
- Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.Protein science : a publication of the Protein Society · 2024Review
- Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1.Nature communications · 2023Article
- Article
- Accelerating Cryptic Pocket Discovery Using AlphaFold.Journal of chemical theory and computation · 2023Article
- Structural basis of efficacy-driven ligand selectivity at GPCRs.Nature chemical biology · 2023Article
Corrections and comments
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Authors and funding
13 authors at 6 institutions in 2 countries.
Funding
Abstract
Allosteric modulators are highly desirable as drugs, particularly for G-protein-coupled receptor (GPCR) targets, because allosteric drugs can achieve selectivity between closely related receptors. The mechanisms by which allosteric modulators achieve selectivity remain elusive, however, particularly given recent structures that reveal similar allosteric binding sites across receptors. Here we show that positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (mAChR) achieve exquisite selectivity by occupying a dynamic pocket absent in existing crystal structures. This cryptic pocket forms far more frequently in molecular dynamics simulations of the M1 mAChR than in those of other mAChRs. These observations reconcile mutagenesis data that previously appeared contradictory. Further mutagenesis experiments validate our prediction that preventing cryptic pocket opening decreases the affinity of M1-selective PAMs. Our findings suggest opportunities for the design of subtype-specific drugs exploiting cryptic pockets that open in certain receptors but not in other receptors with nearly identical static structures.
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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.