ArticleBiophysical journal2015
Allosteric effects of sodium ion binding on activation of the m3 muscarinic g-protein-coupled receptor.
Article in Biophysical journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 90 citations in OpenAlex.
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- Characterization of Posttranslationally Modified PHF-1 Tau Peptides Using Gaussian Accelerated Molecular Dynamics Simulation.Methods in molecular biology (Clifton, N.J.) · 2024Article
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- Predicting Biomolecular Binding Kinetics: A Review.Journal of chemical theory and computation · 2023Review
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- Deep Learning Dynamic Allostery of G-Protein-Coupled Receptors.Research square · 2023Article
- Deep Learning Dynamic Allostery of G-Protein-Coupled Receptors.bioRxiv : the preprint server for biology · 2023Article
- Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex.Nature communications · 2022Article
- Unique features of different classes of G-protein-coupled receptors revealed from sequence coevolutionary and structural analysis.Proteins · 2022Article
- Challenges and frontiers of computational modelling of biomolecular recognition.QRB discovery · 2022Article
- Binding Analysis Using Accelerated Molecular Dynamics Simulations and Future Perspectives.Advances and applications in bioinformatics and chemistry : AABC · 2022Review
- In Silico Identification of Cholesterol Binding Motifs in the Chemokine Receptor CCR3.Membranes · 2021Article
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- Deciphering collaborative sidechain motions in proteins during molecular dynamics simulations.Scientific reports · 2020Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
G-protein-coupled receptors (GPCRs) are important membrane proteins that mediate cellular signaling and represent primary targets for about one-third of currently marketed drugs. Recent x-ray crystallographic studies identified distinct conformations of GPCRs in the active and inactive states. An allosteric sodium ion was found bound to a highly conserved D2.50 residue in inactive GPCRs, whereas the D2.50 allosteric pocket became collapsed in active GPCR structures. However, the dynamic mechanisms underlying these observations remain elusive. In this study, we aimed to understand the mechanistic effects of sodium ion binding on dynamic activation of the M3 muscarinic GPCR through long-timescale accelerated molecular dynamics (aMD) simulations. Results showed that with the D2.50 residue deprotonated, the M3 receptor is bound by an allosteric sodium ion and confined mostly in the inactive state with remarkably reduced flexibility. In contrast, the D2.50-protonated receptor does not exhibit sodium ion binding to the D2.50 allosteric site and samples a significantly larger conformational space. The receptor activation is captured and characterized by large-scale structural rearrangements of the transmembrane helices via dynamic hydrogen bond and salt bridge interactions. The residue motions are highly correlated during receptor activation. Further network analysis revealed that the allosteric signaling between residue D2.50 and key residues in the intracellular, extracellular, and orthosteric pockets is significantly weakened upon sodium ion binding.
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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.