Probing the Hydrophobic Binding Pocket of G-Protein-Coupled Lysophosphatidylserine Receptor GPR34/LPS1 by Docking-Aided Structure?Activity Analysis
Probing the Hydrophobic Binding Pocket of G-Protein-Coupled Lysophosphatidylserine Receptor GPR34/LPS1 by Docking-Aided Structure?Activity Analysis
复制标题
通过对接辅助结构探测G蛋白偶联溶血磷脂酰丝氨酸受体GPR34/LPS1的疏水结合袋？活性分析
DOI：
10.1021/acs.jmedchem.7b00693
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发表时间：
2017
影响因子：
7.3
通讯作者：
Ohwada Tomohiko
中科院分区：
文献类型：
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作者：
Sayama Misa;Inoue Asuka;Nakamura Sho;Jung Sejin;Ikubo Masaya;Otani Yuko;Uwamizu Akiharu;Kishi Takayuki;Makide Kumiko;Aoki Junken;Hirokawa Takatsugu;Ohwada Tomohiko
某些 G 蛋白偶联受体 (GPCR) 的配体已被鉴定为内源性脂质，例如溶血磷脂酰丝氨酸 (LysoPS)。在这里，我们分析了 LysoPS 受体亚型之一 GPR34 配体结构-活性关系的分子基础，重点关注疏水口袋对长链脂肪酸部分的识别。通过将苯环引入 2-deoxy-LysoPS 的脂肪酸部分，我们探索了结合位点对疏水形状的偏好。末端芳香族部分经过修饰的含三苯脂肪酸替代物显示出对 GPR34 的有效激动活性。这些衍生物与基于同源建模/分子动力学的 GPR34 虚拟结合位点的计算对接表明，基于苯的脂质替代物中的扭结与 GPR34 的 L 形疏水袋相匹配。在末端苯环的 4 位上带有大叔丁基的基于四苯的脂质类似物表现出有效的 GPR34 激动活性，验证了当前的疏水结合袋模型。
The ligands of certain G-protein-coupled receptors (GPCRs) have been identified as endogenous lipids, such as lysophosphatidylserine (LysoPS). Here, we analyzed the molecular basis of the structure–activity relationship of ligands of GPR34, one of the LysoPS receptor subtypes, focusing on recognition of the long-chain fatty acid moiety by the hydrophobic pocket. By introducing benzene ring(s) into the fatty acid moiety of 2-deoxy-LysoPS, we explored the binding site’s preference for the hydrophobic shape. A tribenzene-containing fatty acid surrogate with modifications of the terminal aromatic moiety showed potent agonistic activity toward GPR34. Computational docking of these derivatives with a homology modeling/molecular dynamics-based virtual binding site of GPR34 indicated that a kink in the benzene-based lipid surrogates matches the L-shaped hydrophobic pocket of GPR34. A tetrabenzene-based lipid analogue bearing a bulkytert-butyl group at the 4-position of the terminal benzene ring exhibited potent GPR34 agonistic activity, validating the present hydrophobic binding pocket model.