Crystal structure of a lipid G protein-coupled receptor.
Crystal structure of a lipid G protein-coupled receptor.
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DOI：
10.1126/science.1215904
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发表时间：
2012-02-17
期刊：
影响因子：
--
通讯作者：
Stevens RC
中科院分区：
文献类型：
--
作者：
Hanson MA;Roth CB;Jo E;Griffith MT;Scott FL;Reinhart G;Desale H;Clemons B;Cahalan SM;Schuerer SC;Sanna MG;Han GW;Kuhn P;Rosen H;Stevens RC
溶磷脂鞘氨醇1-磷酸通过激活g蛋白偶联的鞘氨醇1-磷酸受体，调节淋巴细胞运输、内皮细胞发育和完整性、心率、血管张力和成熟。在这里，我们展示了鞘磷脂1-磷酸受体1与t4溶菌酶（S1P1-T4L）融合的晶体结构，并与拮抗剂鞘脂模拟物结合。进入结合袋的途径被受体的n端和细胞外环完全阻断。通过配体在受体的跨膜区域内从螺旋I和螺旋VII之间横向进入获得通路。这种结构，连同诱变、激动剂结构-活性关系数据和建模，提供了分子识别和疏水体积触发的详细视图，激活S1P1导致免疫和基质细胞反应的调节。
The lyso-phospholipid sphingosine 1-phosphate modulates lymphocyte trafficking, endothelial development and integrity, heart rate, and vascular tone and maturation by activating G-protein-coupled sphingosine 1-phosphate receptors. Here we present the crystal structure of the sphingosine 1-phosphate receptor 1 fused to T4-lysozyme (S1P1-T4L) in complex with an antagonist sphingolipid mimic. Access to the binding pocket is completely occluded by the N-terminus and extracellular loops of the receptor. Access is gained by ligands entering laterally between helices I and VII within the transmembrane region of the receptor. This structure, along with mutagenesis, agonist structure-activity relationship data and modeling, provides a detailed view of the molecular recognition and hydrophobic volume triggering that activates S1P1 resulting in the modulation of immune and stromal cell responses.
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