Endogenous agonist-bound S1PR3 structure reveals determinants of G protein-subtype bias.
Endogenous agonist-bound S1PR3 structure reveals determinants of G protein-subtype bias.
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DOI：
10.1126/sciadv.abf5325
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发表时间：
2021-06
期刊：
影响因子：
13.6
通讯作者：
Hagiwara M
中科院分区：
文献类型：
--
作者：
Maeda S;Shiimura Y;Asada H;Hirata K;Luo F;Nango E;Tanaka N;Toyomoto M;Inoue A;Aoki J;Iwata S;Hagiwara M
活性S1PR3结构揭示了独特的配体结合模式和信号选择性切换机制。鞘氨醇-1-磷酸（S1P）通过其同源受体（S1PR1至S1PR5）调节许多重要的生理功能，包括免疫反应和血管完整性；然而，尚不清楚S1P如何在结合时激活s1pr。在这里，我们以3.2-Å分辨率测定了人类活性S1PR3及其天然激动剂S1P复合物的晶体结构。S1P在长隧道中呈不弯曲构象，斜穿受体。与无活性的S1PR1结构相比，S1P的烷基尾部周围的四个残基（“四重奏核心”）表现出协调的旋转体变化，以容纳该部分，从而诱导活性构象。此外，我们发现四方核决定了S1PR3的G蛋白选择性。这些结果提供了对G蛋白偶联受体激活和偏倚信号传导的结构基础的深入了解，并将有助于设计偏倚配体以优化治疗方法。
Active S1PR3 structure reveals the unique ligand-binding mode and signaling selectivity switching mechanism. Sphingosine-1-phosphate (S1P) regulates numerous important physiological functions, including immune response and vascular integrity, via its cognate receptors (S1PR1 to S1PR5); however, it remains unclear how S1P activates S1PRs upon binding. Here, we determined the crystal structure of the active human S1PR3 in complex with its natural agonist S1P at 3.2-Å resolution. S1P exhibits 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”) exhibit orchestrating rotamer changes that accommodate the moiety, thereby inducing an active conformation. In addition, we reveal that the quartet core determines G protein selectivity of S1PR3. These results offer insight into the structural basis of activation and biased signaling in G protein–coupled receptors and will help the design of biased ligands for optimized therapeutics.
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影响因子：
7.3
作者：
Galvani S;Sanson M;Blaho VA;Swendeman SL;Obinata H;Conger H;Dahlbäck B;Kono M;Proia RL;Smith JD;Hla T
通讯作者：
Hla T
影响因子：
64.5
作者：
Inoue, Asuka;Raimondi, Francesco;Russell, Robert B.
通讯作者：
Russell, Robert B.
影响因子：
6.8
作者：
Filipek, Slawomir
通讯作者：
Filipek, Slawomir
影响因子：
64.8
作者：
Hua T;Vemuri K;Nikas SP;Laprairie RB;Wu Y;Qu L;Pu M;Korde A;Jiang S;Ho JH;Han GW;Ding K;Li X;Liu H;Hanson MA;Zhao S;Bohn LM;Makriyannis A;Stevens RC;Liu ZJ
通讯作者：
Liu ZJ
DOI：
10.1126/science.aar5551
发表时间：
2019-10-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cartier A;Hla T
通讯作者：
Hla T