Fig. 3. Comparison of recognition modes of chemically distinct agonists by S1PR1.

a–c Structural basis underlying the recognition of cenerimod (dark orange) with polar-neutral headgroup (a), ozanimod (lime green) with polar-basic headgroup (b), and selective SEW2871 (orchid) without classic polar headgroup (c) by S1PR1. d–f Cut away view of different ligand-binding cavities for cenerimod-bound (d), ozanimod-bound (e), and SEW2871-bound S1PR1 (f). g–j The sub-pocket in the orthosteric site of S1PR, which is composed of the residues C206^5.43, T207^5.44, F210^5.47, L272^6.51 and F273^6.52 from TM5 and TM6, respectively, accommodates different moieties from four chemically distinct agonists, including trifluoromethyl moiety, methoxy moiety or cyano-moiety.