ArticleNature communications2024
Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- How Functional Variants Reconfigure the Rac2 Conformational Landscape.The journal of physical chemistry. B · 2026Article
- Mechanistic basis of G595R-mediated resistance to entrectinib in TRK kinase: a structural-energetic perspective.Journal of molecular modeling · 2026Article
- G protein selectivity in group I metabotropic glutamate receptors.Science advances · 2026Article
- Cryptic pockets in proteins: Harnessing conformational dynamics for rational drug design.Acta pharmaceutica Sinica. B · 2026Article
- Mechanistic basis of N-terminal domain-mediated allostery in SIRT6: integrating molecular dynamics simulations and biochemical assays.Molecular diversity · 2026Article
- Assessing the Performance of BioEmu in Understanding Protein Dynamics.International journal of molecular sciences · 2026Article
- Mapping partial agonism of mitragynine at the µ-opioid receptor through molecular dynamics and Markov state modelling analysis.Scientific reports · 2026Article
- Article
- All roads lead to Rome: Emergence of Mechanistic Divergence Shapes Activation of Class B1 G-Protein Coupled Receptors.bioRxiv : the preprint server for biology · 2026Article
- Exploring the distinct activation mechanisms of neuromedin B receptor through multiple replica molecular dynamics simulations and Markov state modeling.Acta pharmacologica Sinica · 2025Article
- Unveiling the molecular mechanism of GProtein science : a publication of the Protein Society · 2025Article
- Mechanistic Insights into the Mechanism of Allosteric Inhibition of Ubiquitin-Specific Protease 7 (USP7).Biomolecules · 2025Article
- Computational Elucidation of a Monobody Targeting the Phosphatase Domain of SHP2.Biomolecules · 2025Article
- mTOR Variants Activation Discovers PI3K-like Cryptic Pocket, Expanding Allosteric, Mutant-Selective Inhibitor Designs.Journal of chemical information and modeling · 2025Article
- Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5.Nature communications · 2024Article
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Two-thirds of signaling hormones and one-third of approved drugs exert their effects by binding and modulating the G protein-coupled receptors (GPCRs) activation. While the activation mechanism for monomeric GPCRs has been well-established, little is known about GPCRs in dimeric form. Here, by combining transition pathway generation, extensive atomistic simulation-based Markov state models, and experimental signaling assays, we reveal an asymmetric, stepwise millisecond allosteric activation mechanism for the metabotropic glutamate receptor subtype 5 receptor (mGlu5), an obligate dimeric class C GPCR. The dynamic picture is presented that agonist binding induces dimeric ectodomains compaction, amplified by the precise association of the cysteine-rich domains, ultimately loosely bringing the intracellular 7-transmembrane (7TM) domains into proximity and establishing an asymmetric TM6-TM6 interface. The active inter-domain interface enhances their intra-domain flexibility, triggering the activation of micro-switches crucial for downstream signal transduction. Furthermore, we show that the positive allosteric modulator stabilizes both the active inter-domain 7TM interface and an open, extended intra-domain ICL2 conformation. This stabilization leads to the formation of a pseudo-cavity composed of the ICL2, ICL3, TM3, and C-terminus, which facilitates G protein coordination. Our strategy may be generalizable for characterizing millisecond events in other allosteric systems.
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