Sphingosine 1-phosphate analogue recognition and selectivity at S1P4 within the endothelial differentiation gene family of receptors
Sphingosine 1-phosphate analogue recognition and selectivity at S1P4 within the endothelial differentiation gene family of receptors
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DOI：
10.1042/bj20050046
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发表时间：
2005-07-01
影响因子：
4.1
通讯作者：
Parrill, AL
中科院分区：
文献类型：
--
作者：
Inagaki, Y;Pham, TT;Parrill, AL
协同计算和实验研究提供了关于S1P(S1P(4) g蛋白偶联受体识别S1P（1-磷酸鞘氨醇）的结构基础的先前未预料到的细节。与关于S1P(1)受体的报道类似，第三跨膜结构域（位置124和125的R3.28和E3.29）的阳离子和阴离子残基与S1P的磷酸盐和铵形成离子对，这些位置的丙氨酸突变取消了S1P的特异性结合，S1P诱导的受体激活和细胞迁移。与S1P(1)受体的发现不同，在第7跨膜结构域中没有阳离子残基与磷酸盐相互作用。此外，还发现了两个以前未发现的与S1P极性头群的相互作用。第4跨膜结构域4.64位的Trp（186）通过阳离子- π相互作用与S1P的铵基相互作用。位置5.38的Lys（204）与S1P形成离子对。S1P(4)和S1P(1)受体表现出结合袋形状和静电分布的差异，这与已发表的结构-活性关系有关。特别是，mS1P(4)的结合袋（小鼠S1P(4)）具有与非极性尾巴末端等距离的阴离子磷酸基和阳离子铵基的识别位点。相比之下，hS1P(1)（人类S1P(4)）的结合袋比磷酸盐识别位点更靠近非极性尾部末端2埃（1埃= 0.1 nm）。
Synergistic computational and experimental studies provided previously unforeseen details concerning the structural basis of S1P (sphingosine 1-phosphate) recognition by the S1P(4) G-protein-coupled receptor. Similarly to reports on the S1P(1) receptor, cationic and anionic residues in the third transmembrane domain (R3.28 and E3.29 at positions 124 and 125) form ion pairs with the phosphate and ammonium of S1P, and alanine mutations at these positions abolished specific S1P binding, S1P-induced receptor activation and cell migration. Unlike findings on the S1P(1) receptor, no cationic residue in the seventh transmembrane domain interacts with the phosphate. Additionally, two previously undiscovered interactions with the S1P polar headgroup have been identified. Trp(186) at position 4.64 in the fourth transmembrane domain interacts by a cation-pi interaction with the ammonium group of S1P. Lys(204) at position 5.38 forms an ion pair with the S1P. The S1P(4) and S1P(1) receptors show differences in binding-pocket shape and electrostatic distributions that correlate with the published structure-activity relationships. In particular, the binding pocket of mS1P(4) (mouse S1P(4)) has recognition sites for the anionic phosphate and cationic ammonium groups that are equidistant from the end of the non-polar tail. In contrast, the binding pocket of hS1P(1) (human S1P(4)) places the ammonium recognition site 2 angstrom (1 angstrom = 0.1 nm) closer to the end of the non-polar tail than the phosphate recognition site.