Fig. 6: Structural basis of signal bias in S1PR1.

a The orthosteric binding pocket of SAR247799 in S1PR1. SAR247799 is shown in. Gray. b Superposition of SAR247799 and FTY720-P binding modes. c Residue distribution by functional relevance and its impact on efficacy and potency. The ligands contact with residues of S1PR1 within 4.2 Å. Polar interactions are highlighted as red dashed lines. d Schematic of interactions between SAR247799 and S1PR1. Residues contacting with both SAR247799 and FTY720-P are shown in pink ovals, and only with SAR247799 are displayed in blue ovals. e Key residues are shown in sticks and colored in light green (SAR247799-bound S1PR1) and orange (FTY720-P-bound S1PR1). f Representative curve for effects of the S1PR1 R120^3.28 and E121^3.29 mutations on SAR247799 and FTY720g-P induced G_αi1-G_γ2 dissociation assay and β-arrestin2 recruitment in CHO cells. Data represent mean ± SEM from three independent experiments. g Bias factors of representation residues in S1PR1 relative to wild-type induced by SAR247799 and FTY720-P. Data represent mean ± SEM from three independent experiments. All biological experiments were repeated three times and yielded consistent results.