Open AccessStructural insights into sphingosine-1-phosphate receptor activation
Author(s) -
Leiye Yu,
Licong He,
Bing Siang Gan,
Rujuan Ti,
Qicai Xiao,
Hongli Hu,
Lizhe Zhu,
Sheng Wang,
Ruobing Ren
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2117716119
Subject(s) - s1pr1 , sphingosine 1 phosphate receptor , sphingosine , microbiology and biotechnology , g protein coupled receptor , sphingolipid , chemistry , sphingosine kinase , receptor , agonist , biology , sphingosine 1 phosphate , biochemistry , biophysics , cancer research , vascular endothelial growth factor a , vascular endothelial growth factor , vegf receptors
Significance Sphingosine-1-phosphate (S1P) receptors are valid therapeutic targets to treat autoimmune diseases, such as relapsing multiple sclerosis and ulcerative colitis. Particularly, S1PR1 is well characterized because of its nonredundant functions on T and B cells’ egress. However, the activation mechanism of S1PR1 is still poorly understood. Therefore, we determined active S1PR1–Gi complex structures bound to distinct agonists. Phosphorylated Fingolimod [(S)-FTY720-P] could modulate lymphocyte trafficking and treat multiple sclerosis. The nonlipid-like agonist CBP-307 is currently being evaluated in a global phase 2 clinical study in moderate to severe ulcerative colitis and Crohn’s disease. Meanwhile, two binding poses of CBP-307 and the unoccupied subpocket we observed may provide opportunities to improve further the efficacy and specificity of CBP-307 targeting different S1P receptors.