[1P-1] Poster 1 (1P-01ー1P-48)

[1P-09*] Structural analysis of active sphingosine-1-phosphate receptor

^○Shintaro Maeda^1,2, Yuki Shiimura^3,4, Hidetsugu Asada³, Kunio Hirata⁵, Fangjia Luo⁵, Eriko Nango^5,6, Asuka Inoue⁷, So Iwata^5,6, Masatoshi Hagiwara¹ (1.Dept. of Drug Discov. Med., Kyoto Univ., 2.Dept. of Anat. and Dev. Bio., Kyoto Univ., 3.Dept. of Cell Bio., Kyoto Univ., 4.Inst. Life Sci. Kurume Univ., 5.Riken SPring-8, 6.Inst. Multidiscip. Res. for Adv. Mat. Tohoku Univ., 7.Dept. Mol. Cell Biochem. Tohoku Univ.)

Sphingosine-1-phosphate (S1P) regulates important physiological functions, including the immune response and vascular integrity, via its cognate receptors (S1PR1-5); however, it remains unclear how S1P activates S1PRs upon binding. Here, we determined the crystal structure of active human S1PR3 in complex with its natural agonist S1P at 3.1-angstrole resolution. S1P shows an unbent conformation in the long tunnel, which penetrates through the receptor obliquely. Compared with the inactive S1PR1 structure, four residues surrounding the alkyl tail of S1P (the "quartet core") show orchestrating rotamer changes that accommodate the moiety, thereby inducing an active conformation. Additionally, we reveal that the quartet core determines the G protein selectivity of S1PR3. These results offer insight into the structural basis of activation and biased signalling in G protein-coupled receptors and will help the design of biased ligands for optimized therapeutics.