ArticleProceedings of the National Academy of Sciences of the United States of America2022
Structural insights into sphingosine-1-phosphate 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. An erratum has been issued. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 58 citations in OpenAlex.
- A cell-free lipid sterosomal therapeutic enables bone regeneration via USP18-mediated noncanonical S1P signaling.Bioactive materials · 2026Article
- Insights into the binding mechanism and structural requirements of LPAR2 antagonists as antifibrotic agents based on homology modeling, molecular docking, prediction of membrane permeability and 3D QSAR.Journal of computer-aided molecular design · 2026Article
- Structural insights into subtype-specific agonist recognition by sphingosine-1-phosphate receptors.PLoS biology · 2026Article
- Structural and dynamic insights into agonist recognition and function of the thromboxane ANature communications · 2026Article
- Hidden Interactions: Quantum Perspectives in Drug Design.Methods in molecular biology (Clifton, N.J.) · 2026Review
- Computational screening and in vitro evaluation of sphingosine-1-phosphate analogues as therapeutics for Non-Hodgkin's lymphoma.Scientific reports · 2025Article
- The novel sphingosine-1-phosphate receptor modulator KRP-203 prevents myocardial ischemia-reperfusion injury by preserving mitochondrial function through activation of the RISK and SAFE signaling pathways.Cell biology and toxicology · 2025Article
- Structural insights into the G-protein subtype selectivity revealed by human sphingosine-1-phosphate receptor 3-GProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Membrane disruption attenuates agonist potency in prostanoid receptors.The Biochemical journal · 2025Article
- Efficient Characterization of GPCRs Allosteric Modulation: Application to the Rational Design of De Novo S1PR1 Allosteric Modulators.Journal of chemical information and modeling · 2025Article
- SIMPLEX Enriches Hydrophobic and Lipidated Proteins in Membrane Proteomics Experiments.Proteomics · 2025Article
- Structural basis for lipid-mediated activation of G protein-coupled receptor GPR55.Nature communications · 2025Article
- S1PR1-biased activation drives the resolution of endothelial dysfunction-associated inflammatory diseases by maintaining endothelial integrity.Nature communications · 2025Article
- A review of large language models and autonomous agents in chemistry.Chemical science · 2025Review
- Possible Involvement of Lysophospholipids in Severe Asthma as Novel Lipid Mediators.Biomolecules · 2025Review
- Sphingosine-1-Phosphate Metabolic Pathway in Cancer: Implications for Therapeutic Targets.International journal of molecular sciences · 2025Review
- Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2.Nature communications · 2025Article
- Deciphering the role of sphingosine 1-phosphate in central nervous system myelination and repair.Journal of neurochemistry · 2025Review
- Protective Role of Sphingosine-1-Phosphate During Radiation-Induced Testicular Injury.Antioxidants (Basel, Switzerland) · 2024Review
- Targeting sphingosine 1-phosphate and sphingosine kinases in pancreatic cancer: mechanisms and therapeutic potential.Cancer cell international · 2024Review
Corrections and comments
- Erratum issued
Authors and funding
9 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1 to S1PR5, encoded in the human genome, and their activities are governed by endogenous S1P, lipid-like S1P mimics, or nonlipid-like therapeutic molecules. Among S1PRs, S1PR1 stands out due to its nonredundant functions, such as the egress of T and B cells from the thymus and secondary lymphoid tissues, making it a potential therapeutic target. However, the structural basis of S1PR1 activation and regulation by various agonists remains unclear. Here, we report four atomic resolution cryo-electron microscopy (cryo-EM) structures of Gi-coupled human S1PR1 complexes: bound to endogenous agonist d18:1 S1P, benchmark lipid-like S1P mimic phosphorylated Fingolimod [(S)-FTY720-P], or nonlipid-like therapeutic molecule CBP-307 in two binding modes. Our results revealed the similarities and differences of activation of S1PR1 through distinct ligands binding to the amphiphilic orthosteric pocket. We also proposed a two-step “shallow to deep” transition process of CBP-307 for S1PR1 activation. Both binding modes of CBP-307 could activate S1PR1, but from shallow to deep transition may trigger the rotation of the N-terminal helix of Gαi and further stabilize the complex by increasing the Gαi interaction with the cell membrane. We combine with extensive biochemical analysis and molecular dynamic simulations to suggest key steps of S1P binding and receptor activation. The above results decipher the common feature of the S1PR1 agonist recognition and activation mechanism and will firmly promote the development of therapeutics targeting S1PRs.
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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.