Structural insights into subtype-specific agonist recognition by sphingosine-1-phosphate receptors

  • PLoS Biol. 2026 Apr 10;24(4):e3003381. doi: 10.1371/journal.pbio.3003381.
Leiye Yu  1  2 ,  Haizhan Jiao  3 ,  Bin Pang  1 ,  Rujuan Ti  4 ,  Bing Gan  1 ,  Zhaoyang Qin  1 ,  Jinxin Wang  5 ,  Lizhe Zhu  4 ,  Hongli Hu  3 ,  Ruobing Ren  1
Affiliations
  • 1. Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China.
  • 2. Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong (Shenzhen), Shenzhen, China.
  • 4. Warshal Institute of Computational Biology, School of Life and Health Sciences, The Chinese University of Hong Kong (Shenzhen), Shenzhen, China.
  • 5. School of Pharmacy, Second Military Medical University, Shanghai, China.
PMID: 41961881 DOI: 10.1371/journal.pbio.3003381
Abstract

Sphingosine-1-phosphate (S1P), a key metabolite of sphingolipids, plays crucial roles in a wide range of physiological and pathological processes. S1P primarily exerts its functions by binding to G protein-coupled sphingosine-1-phosphate receptors (S1PRs), which comprise five subtypes (S1PR1-5) in humans, thereby activating these receptors and their downstream signaling pathways. Understanding the molecular determinants that govern agonist selectivity among different S1PR subtypes is vital for the rational and precise development of targeted therapeutic agents. Here, four cryo-electron microscopy structures of agonist-bound S1PR1-Gi1 complexes are reported. Through an integrated approach combining structural analysis, molecular dynamics simulations, and pharmacological assays, the molecular basis for the selectivity of CYM5442, HY-X-1011, Ponesimod, and SAR247799 toward S1PR1 over S1PR2-S1PR5 is uncovered. Nonconserved residues within the ligand-binding pocket and at the Gi1-protein interface contribute to S1PR1 selectivity by these agonists. A distinct agonist binding orientation toward transmembrane helices 5-7, combined with branched substituents that increase the agonist's molecular width, results in steric clashes with residues in S1PR3. Additionally, branched moieties located at the tail portions of the agonist restrict its deep insertion into the binding pocket of both S1PR3 and S1PR5. These structural features collectively enhance its selectivity for S1PR1 over S1PR3 and S1PR5. Furthermore, polar interactions with conserved polar residues in the top region of the binding pocket also influence agonist selectivity. Besides, the relatively broad molecular width of the agonist sterically hinders its binding into S1PR2 and S1PR4 pocket by nonconserved residue pairs bearing bulky side chains. These findings establish a structural framework for the rational design of next-generation S1PR1 highly selective agonists with improved therapeutic potential.

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