Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster , Corrensstraße 48, D-48149 Münster, Germany.
Biochemistry. 2014 May 13;53(18):2993-3003. doi: 10.1021/bi401575g. Epub 2014 Apr 28.
The σ1 receptor is an integral membrane protein that shares no homology with other receptor systems, has no unequivocally identified natural ligands, but appears to play critical roles in a wide variety of cell functions. While the number of reports of the possible functions of the σ1 receptor is increasing, almost no information about the three-dimensional structure of the receptor and/or possible modes of interaction of the σ1 protein with its ligands have been described. Here we performed an in vitro/in silico investigation to analyze the molecular interactions of the σ1 receptor with its prototypical agonist (+)-pentazocine. Accordingly, 23 mutant σ1 isoforms were generated, and their interactions with (+)-pentazocine were determined experimentally. All direct and/or indirect effects exerted by the mutant residues on the receptor-agonist interactions were reproduced and rationalized in silico, thus shining new light on the three-dimensional structure of the σ1 receptor and its ligand binding site.
σ1 受体是一种完整的膜蛋白，与其他受体系统没有同源性，没有明确鉴定的天然配体，但似乎在各种细胞功能中发挥关键作用。虽然关于 σ1 受体可能功能的报道数量正在增加，但几乎没有关于受体的三维结构和/或 σ1 蛋白与其配体可能相互作用模式的信息。在这里，我们进行了体外/计算机模拟研究，以分析 σ1 受体与其原型激动剂 (+)-戊甲噻嗪的分子相互作用。因此，生成了 23 种突变 σ1 同工型，并通过实验确定了它们与 (+)-戊甲噻嗪的相互作用。突变残基对受体-激动剂相互作用的所有直接和/或间接影响都在计算机模拟中得到了重现和合理化，从而为 σ1 受体及其配体结合位点的三维结构提供了新的线索。
