[1FT-1] 構造生物学 (1P-01～1P-25)

[1P-09*] 活性型スフィンゴシン-1-リン酸受容体の結晶構造解析

^○前田 信太郎^1,2, 椎村 祐樹^3,4, 浅田 秀基³, 平田 邦生⁵, Fangjia Luo⁵, 南後 恵理子^5,6, 井上 飛鳥⁷, 岩田 想^5,6, 萩原 正敏¹ (1.京大・医・創薬, 2.京大・医・形態, 3.京大・医・分子, 4.久留米大・分生研, 5.理研・SPring-8, 6.東北大・多元研, 7.東北大・薬・生化)

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.