ArticleProceedings of the National Academy of Sciences of the United States of America2022
Hydration-mediated G-protein-coupled receptor activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 24 citations in OpenAlex.
- Atomic, structural and molecular insights into GPCR ligand binding and signalling.Nature reviews. Molecular cell biology · 2026Review
- Structured water molecules drive activation and G protein selectivity in the GPR174 receptor.PLoS biology · 2026Article
- Structural analysis reveals that water molecules mediate self-activation of GPR99.Communications biology · 2026Article
- HInternational journal of molecular sciences · 2025Review
- Detection of Putative Ligand Dissociation Pathways in Proteins Using Site-Identification by Ligand Competitive Saturation.Journal of chemical information and modeling · 2025Article
- Histamine-modulated wettability switching in G-protein-coupled receptor inspired nanochannel for potential drug screening and biosensing.Nature communications · 2025Article
- Hidden water's influence on rhodopsin activation.Biophysical journal · 2024Review
- Cell swelling enhances ligand-driven β-adrenergic signaling.Nature communications · 2024Article
- Influence of the Water Model on the Structure and Interactions of the GPR40 Protein with the Lipid Membrane and the Solvent: Rigid versus Flexible Water Models.Journal of chemical theory and computation · 2024Article
- Membrane Mimetic-Dependence of GPCR Energy Landscapes.bioRxiv : the preprint server for biology · 2023Article
- Three-Dimensional Structural Insights Have Revealed the Distinct Binding Interactions of Agonists, Partial Agonists, and Antagonists with the µ Opioid Receptor.International journal of molecular sciences · 2023Review
- Protons taken hostage: Dynamic H-bond networks of the pH-sensing GPR68.Computational and structural biotechnology journal · 2023Article
- Mechanistic basis of GPCR activation explored by ensemble refinement of crystallographic structures.Protein science : a publication of the Protein Society · 2022Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 2 countries.
Funding
Abstract
The Rhodopsin family of G-protein–coupled receptors (GPCRs) comprises the targets of nearly a third of all pharmaceuticals. Despite structural water present in GPCR X-ray structures, the physiological relevance of these solvent molecules to rhodopsin signaling remains unknown. Here, we show experimental results consistent with the idea that rhodopsin activation in lipid membranes is coupled to bulk water movements into the protein. To quantify hydration changes, we measured reversible shifting of the metarhodopsin equilibrium due to osmotic stress using an extensive series of polyethylene glycol (PEG) osmolytes. We discovered clear evidence that light activation entails a large influx of bulk water (∼80–100 molecules) into the protein, giving insight into GPCR activation mechanisms. Various size polymer osmolytes directly control rhodopsin activation, in which large solutes are excluded from rhodopsin and dehydrate the protein, favoring the inactive state. In contrast, small osmolytes initially forward shift the activation equilibrium until a quantifiable saturation point is reached, similar to gain-of-function protein mutations. For the limit of increasing osmolyte size, a universal response of rhodopsin to osmotic stress is observed, suggesting it adopts a dynamic, hydrated sponge-like state upon photoactivation. Our results demand a rethinking of the role of water dynamics in modulating various intermediates in the GPCR energy landscape. We propose that besides bound water, an influx of bulk water plays a necessary role in establishing the active GPCR conformation that mediates signaling.
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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.