ArticleACS chemical neuroscience2014
Identification of specific ligand-receptor interactions that govern binding and cooperativity of diverse modulators to a common metabotropic glutamate receptor 5 allosteric site.
Article in ACS chemical neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Transmembrane Domain Dominance Drives Emergent Signaling and Allosteric Inversion in mGlubioRxiv : the preprint server for biology · 2026Article
- Metabotropic glutamate receptors: Allosteric structural modulation and new treatments for anxiety disorders.Neurosciences (Riyadh, Saudi Arabia) · 2025Review
- Conformational diversity in class C GPCR positive allosteric modulation.Nature communications · 2025Article
- Pharmacology, Signaling and Therapeutic Potential of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators.ACS pharmacology & translational science · 2024Review
- Article
- Metabotropic Glutamate Receptor Subtype 5 Positron-Emission-Tomography Radioligands as a Tool for Central Nervous System Drug Development: Between Progress and Setbacks.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations.Cell reports · 2021Article
- Structures of GNature · 2021Article
- Allosteric Molecular Switches in Metabotropic Glutamate Receptors.ChemMedChem · 2021Review
- Detailed In Vitro Pharmacological Characterization of Clinically Tested Negative Allosteric Modulators of the Metabotropic Glutamate Receptor 5.Molecular pharmacology · 2020Article
- Exploring the Activation Mechanism of the mGlu5 Transmembrane Domain.Frontiers in molecular biosciences · 2020Article
- Computational Drug Design Applied to the Study of Metabotropic Glutamate Receptors.Molecules (Basel, Switzerland) · 2019Review
- Molecular Imaging of mGluR5 Availability with [Cellular and molecular neurobiology · 2019Article
- BCL::MolAlign: Three-Dimensional Small Molecule Alignment for Pharmacophore Mapping.Journal of chemical information and modeling · 2019Article
- Identification of Global and Ligand-Specific Calcium Sensing Receptor Activation Mechanisms.Molecular pharmacology · 2018Article
- A genome-wide quantitative trait locus (QTL) linkage scan of NEO personality factors in Latino families segregating bipolar disorder.American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics · 2017Article
- Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand.Scientific reports · 2017Article
- Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery.Neuropharmacology · 2017Article
- Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias.British journal of pharmacology · 2016Review
- Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.Chemical reviews · 2016Review
Corrections and comments
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Authors and funding
15 authors.
Funding
Abstract
A common metabotropic glutamate receptor 5 (mGlu5) allosteric site is known to accommodate diverse chemotypes. However, the structural relationship between compounds from different scaffolds and mGlu5 is not well understood. In an effort to better understand the molecular determinants that govern allosteric modulator interactions with mGlu5, we employed a combination of site-directed mutagenesis and computational modeling. With few exceptions, six residues (P654, Y658, T780, W784, S808, and A809) were identified as key affinity determinants across all seven allosteric modulator scaffolds. To improve our interpretation of how diverse allosteric modulators occupy the common allosteric site, we sampled the wealth of mGlu5 structure-activity relationship (SAR) data available by docking 60 ligands (actives and inactives) representing seven chemical scaffolds into our mGlu5 comparative model. To spatially and chemically compare binding modes of ligands from diverse scaffolds, the ChargeRMSD measure was developed. We found a common binding mode for the modulators that placed the long axes of the ligands parallel to the transmembrane helices 3 and 7. W784 in TM6 not only was identified as a key NAM cooperativity determinant across multiple scaffolds, but also caused a NAM to PAM switch for two different scaffolds. Moreover, a single point mutation in TM5, G747V, altered the architecture of the common allosteric site such that 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU29) was noncompetitive with the common allosteric site. Our findings highlight the subtleties of allosteric modulator binding to mGlu5 and demonstrate the utility in incorporating SAR information to strengthen the interpretation and analyses of docking and mutational data.
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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.