ArticleThe Journal of biological chemistry2014
Molecular mechanisms of bitopic ligand engagement with 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 26 papers.
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Who cites it
26 citing papers in PubMed, 64 citations in OpenAlex.
- Biased Allosteric Modulation in GPCR Drug Discovery.Handbook of experimental pharmacology · 2026Review
- Deciphering complexity of GPCR signaling and modulation: implications and perspectives for drug discovery.Clinical science (London, England : 1979) · 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
- A critical re-evaluation of the slope factor of the operational model of agonism: When to exponentiate operational efficacy.Scientific reports · 2023Article
- Recessive CHRM5 variant as a potential cause of neurogenic bladder.American journal of medical genetics. Part A · 2023Article
- Insertion of Nanoluc into the Extracellular Loops as a Complementary Method To Establish BRET-Based Binding Assays for GPCRs.ACS pharmacology & translational science · 2022Article
- In Search of Synergistic Insect Repellents: Modeling of Muscarinic GPCR Interactions with Classical and Bitopic Photoactive Ligands.Molecules (Basel, Switzerland) · 2022Article
- Crystal structure of the αNature communications · 2022Article
- Design, synthesis and biological evaluation of novel orthosteric-allosteric ligands of the cannabinoid receptor type 2 (CBFrontiers in chemistry · 2022Article
- Identification of a Novel Allosteric Site at the MACS chemical neuroscience · 2021Article
- Enantioenriched Positive Allosteric Modulators Display Distinct Pharmacology at the Dopamine DMolecules (Basel, Switzerland) · 2021Article
- Restoring Agonist Function at a Chemogenetically Modified MACS chemical neuroscience · 2020Article
- The Role of Orthosteric Building Blocks of Bitopic Ligands for Muscarinic M1 Receptors.ACS omega · 2020Article
- 2016 Philip S. Portoghese Medicinal Chemistry Lectureship: Designing Bivalent or Bitopic Molecules for G-Protein Coupled Receptors. The Whole Is Greater Than the Sum of Its Parts.Journal of medicinal chemistry · 2020Article
- Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias.Frontiers in pharmacology · 2020Review
- Bitopic Inhibition of ATP and Substrate Binding in Ser/Thr Kinases through a Conserved Allosteric Mechanism.Biochemistry · 2018Article
- Importance of the second extracellular loop for melatonin MTBritish journal of pharmacology · 2018Article
- Probing the binding site of novel selective positive allosteric modulators at the MBiochemical pharmacology · 2018Article
- MNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2018Article
- Bitopic Binding Mode of an MMolecular pharmacology · 2018Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
TBPB and 77-LH-28-1 are selective agonists of the M1 muscarinic acetylcholine receptor (mAChR) that may gain their selectivity through a bitopic mechanism, interacting concomitantly with the orthosteric site and part of an allosteric site. The current study combined site-directed mutagenesis, analytical pharmacology,and molecular modeling to gain further insights into the structural basis underlying binding and signaling by these agonists. Mutations within the orthosteric binding site caused similar reductions in affinity and signaling efficacy for both selective and prototypical orthosteric ligands. In contrast, the mutation of residues within transmembrane helix (TM) 2 and the second extracellular loop (ECL2) discriminated between the different classes of ligand. In particular, ECL2 appears to be involved in the selective binding of bitopic ligands and in coordinating biased agonism between intracellular calcium mobilization and ERK1/2 phosphorylation. Molecular modeling of the interaction between TBPB and the M1 mAChR revealed a binding pose predicted to extend from the orthosteric site up toward a putative allosteric site bordered by TM2, TM3, and TM7, thus consistent with a bitopic mode of binding. Overall, these findings provide valuable structural and mechanistic insights into bitopic ligand actions and receptor activation and support a role for ECL2 in dictating the active states that can be adopted by a G protein-coupled receptor. This may enable greater selective ligand design and development for mAChRs and facilitate improved identification of bitopic ligands.
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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.