ArticleThe Journal of biological chemistry2014
Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 61 citations in OpenAlex.
- Targeting frizzled receptors (FZDs) for anti-tumor therapy: From orthosteric to allosteric inhibition.Acta pharmaceutica Sinica. B · 2026Review
- Functional Evaluation of Tetrahydroisoquinoline-Derived Ligands Reveals Distinct Modulatory Profiles at the Muscarinic M1 Receptor.ACS medicinal chemistry letters · 2026Article
- Resistance to Allosteric Inhibitors.Journal of molecular biology · 2025Review
- Analysing the effect caused by increasing the molecular volume in M1-AChR receptor agonists and antagonists: a structural and computational study.RSC advances · 2024Article
- Insertion of Nanoluc into the Extracellular Loops as a Complementary Method To Establish BRET-Based Binding Assays for GPCRs.ACS pharmacology & translational science · 2022Article
- Crystal structure of the αNature communications · 2022Article
- Identification of a Novel Allosteric Site at the MACS chemical neuroscience · 2021Article
- Development of Novel 4-Arylpyridin-2-one and 6-Arylpyrimidin-4-one Positive Allosteric Modulators of the MChemMedChem · 2021Article
- The Role of Orthosteric Building Blocks of Bitopic Ligands for Muscarinic M1 Receptors.ACS omega · 2020Article
- Structure and selectivity engineering of the MScience (New York, N.Y.) · 2020Article
- Current Advances in Allosteric Modulation of Muscarinic Receptors.Biomolecules · 2020Review
- Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias.Frontiers in pharmacology · 2020Review
- Cryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs.Nature communications · 2019Article
- Positive Allosteric Modulation of Cholinergic Receptors Improves Spatial Learning after Cortical Contusion Injury in Mice.Journal of neurotrauma · 2019Article
- Applications and limitations of fitting of the operational model to determine relative efficacies of agonists.Scientific reports · 2019Article
- Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic MBritish journal of pharmacology · 2019Article
- Understanding Ligand Binding to G-Protein Coupled Receptors Using Multiscale Simulations.Frontiers in molecular biosciences · 2019Review
- Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors.The Journal of general physiology · 2018Review
- Probing the binding site of novel selective positive allosteric modulators at the MBiochemical pharmacology · 2018Article
- Structure-Activity Relationships of Pan-GαACS chemical neuroscience · 2018Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Benzylquinolone carboxylic acid (BQCA) is an unprecedented example of a selective positive allosteric modulator of acetylcholine at the M1 muscarinic acetylcholine receptor (mAChR). To probe the structural basis underlying its selectivity, we utilized site-directed mutagenesis, analytical modeling, and molecular dynamics to delineate regions of the M1 mAChR that govern modulator binding and transmission of cooperativity. We identified Tyr-85(2.64) in transmembrane domain 2 (TMII), Tyr-179 and Phe-182 in the second extracellular loop (ECL2), and Glu-397(7.32) and Trp-400(7.35) in TMVII as residues that contribute to the BQCA binding pocket at the M1 mAChR, as well as to the transmission of cooperativity with the orthosteric agonist carbachol. As such, the BQCA binding pocket partially overlaps with the previously described "common" allosteric site in the extracellular vestibule of the M1 mAChR, suggesting that its high subtype selectivity derives from either additional contacts outside this region or through a subtype-specific cooperativity mechanism. Mutation of amino acid residues that form the orthosteric binding pocket caused a loss of carbachol response that could be rescued by BQCA. Two of these residues (Leu-102(3.29) and Asp-105(3.32)) were also identified as indirect contributors to the binding affinity of the modulator. This new insight into the structural basis of binding and function of BQCA can guide the design of new allosteric ligands with tailored pharmacological properties.
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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.