Fig. 5. GPR84 activation mechanism.

a, b Superposition of activated GPR84 (cornflower blue) with active S1PR1 (light salmon; PDB code: 7EVY) and inactive S1PR1 (gray; PDB code: 3V2Y). Notable conformational changes occur at intracellular ends of TM6 and TM7 upon receptor activation, side view (a) and top view (b). c N104^3.36 forms hydrogen bond with Y332^6.48 and T359^7.42. d Detailed comparison of activated GPR84(cornflower blue) with inactive S1PR1 (gray; PDB code: 3V2Y) and active S1PR1 (light salmon; PDB code: 7EVY). In particular, side-chains N104^3.36 and Y332^6.48 exhibit similar displacement to L128^3.36, W269^6.48 of S1PR1 upon activation. e, f Dose-response curves of LY237(e) and 3-OH-C12(f) in activating GPR84 with mutations destroying the hydrogen bonds. Data are shown as mean ± S.E.M. from a minimum of three technical replicates, which performed in triplicates. The representative dose-response curves are shown. g The “dual toggle switch” N104^3.36 and Y332^4.48 of GPR84 display relative rotameric change when sensing agonist. h–j The key G-I-F^6.44(PIF motif in common GPCRs) (h), G-R^3.50-Y(D(E)RY motif in common GPCRs) (i), and N-P^7.50-xx-Y^7.53 ( j) motifs displayed conformational rearrangement in activated GPR84. Source data are provided as a Source data file.