Department of Chemistry, The University of Memphis, 213 Smith Chemistry Building, Memphis, TN 38152, USA.
Sci Signal. 2012 May 22;5(225):pe23. doi: 10.1126/scisignal.2003160.
The sphingosine 1-phosphate receptor 1 (S1P₁) and its ligand, sphingosine 1-phosphate (S1P), have now emerged as critical regulators of lymphocyte trafficking, vascular development and integrity, and immunity. S1P₁ is targeted by the phosphorylation product of fingolimod, which has been approved for the treatment of multiple sclerosis. The recent progress in the structural biology of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors has now enabled the elucidation of the structure of S1P₁. Analysis of the structure, along with structure activity and mutagenesis analysis, highlighted key interactions associated with the binding of S1P and agonists and suggested that the ligand may gain access to the binding pocket by lateral diffusion within the plasma membrane. The S1P₁ crystal structure will be helpful for designing ligands that specifically target S1P₁.
鞘氨醇 1-磷酸受体 1（S1P₁）及其配体鞘氨醇 1-磷酸（S1P）现已成为淋巴细胞迁移、血管发育和完整性以及免疫的关键调节剂。S1P₁是fingolimod 的磷酸化产物的靶标，fingolimod 已被批准用于多发性硬化症的治疗。异三聚体鸟苷酸结合蛋白（G 蛋白）偶联受体的结构生物学的最新进展现在使 S1P₁ 的结构得以阐明。对结构的分析，以及结构活性和突变分析，突出了与 S1P 和激动剂结合相关的关键相互作用，并表明配体可能通过质膜内的侧向扩散进入结合口袋。S1P₁ 晶体结构将有助于设计专门针对 S1P₁ 的配体。
