Fig. 5. Comparison of the activation mechanisms of lysophospholipid receptors.

a Slice through views of the orthosteric ligand binding pockets of S1P₁ when bound with the antagonist ML056 (in yellow), or S1P (in cyan). b Slice through views of the orthosteric ligand binding pockets of LPA₁ in the inactive (in white) or active (in green) states. c–e key residues for S1P₁ activation are shown in sticks to illustrate the rotameric reorganization of their side chains at the bottom of the ligand-binding pocket, when bound with ML056 (c), S1P (d), or Siponimod (e). f, g Key residues for LPA₁ activation are shown in sticks to illustrate the rotameric reorganization of their side chains, when in the inactive unliganded state (f), or in the active LPA-bound state (g). h, i The conformational changes are propagated from the bottom of the ligand-binding pocket to the G-protein binding pocket near TM5 and TM6, in S1P₁ (h) and LPA₁ (i). j–l Dose–response data from cells expressing different S1P₁ constructs after stimulation with S1P or Siponimod. Data are shown as mean ± SEM of three experiments. The analysis was done using the log(agonist) vs. response function of Prism 8 (GraphPad). Source data are provided as a Source Data file.