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Science. 2012 Feb 17;335(6070):851-5. doi: 10.1126/science.1215904.
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 (S1P(1)-T4L) in complex with an antagonist sphingolipid mimic. Extracellular access to the binding pocket is occluded by the amino 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 requirement for hydrophobic volume that activates S1P(1), resulting in the modulation of immune and stromal cell responses.
溶血磷脂神经鞘氨醇 1-磷酸通过激活 G 蛋白偶联神经鞘氨醇 1-磷酸受体调节淋巴细胞迁移、内皮细胞发育和完整性、心率以及血管张力和成熟。在此，我们展示了与拮抗剂鞘脂类似物结合的融合 T4 溶菌酶的神经鞘氨醇 1-磷酸受体 1（S1P（1）-T4L）的晶体结构。受体的氨基末端和细胞外环阻塞了结合口袋的细胞外进入。配体通过进入受体跨膜区域的 I 螺旋和 VII 螺旋之间的横向进入来获得进入。该结构以及诱变、激动剂结构-活性关系数据和建模，提供了 S1P（1）激活的分子识别和疏水性体积要求的详细视图，从而调节免疫和基质细胞反应。
