Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo, 113-0033, Japan.
Commun Biol. 2024 Nov 6;7(1):1444. doi: 10.1038/s42003-024-07152-y.
Lysophosphatidic acid receptor 1 (LPA) is one of the G protein-coupled receptors activated by the lipid mediator, lysophosphatidic acid (LPA). LPA is associated with a variety of diseases, and LPA agonists have potential therapeutic value for treating obesity and depression. Although potent nonlipid LPA agonists have recently been identified, the mechanisms of nonlipid molecule-mediated LPA activation remain unclear. Here, we report a cryo-electron microscopy structure of the human LPA-G complex bound to a nonlipid basic agonist, CpY, which has 30-fold higher agonistic activity as compared with LPA. Structural comparisons of LPA with other lipid GPCRs revealed that the negative charge in the characteristic binding pocket of LPA allows the selective recognition of CpY, which lacks a polar head. In addition, our structure show that the ethyl group of CpY directly pushes W271 to fix the active conformation. Endogenous LPA lacks these chemical features, which thus represent the crucial elements of nonlipid agonists that potently activate LPA. This study provides detailed mechanistic insights into the ligand recognition and activation of LPA by nonlipid agonists, expanding the scope for drug development targeting the LPA receptors.
溶血磷脂酸受体 1（LPA1）是一种 G 蛋白偶联受体，可被脂质介质溶血磷脂酸（LPA）激活。LPA 与多种疾病有关，LPA 激动剂在治疗肥胖症和抑郁症方面具有潜在的治疗价值。尽管最近已经确定了有效的非脂类 LPA 激动剂，但非脂类分子介导的 LPA 激活机制仍不清楚。在这里，我们报告了与非脂类碱性激动剂 CpY 结合的人 LPA-G 复合物的冷冻电子显微镜结构，CpY 的激动活性比 LPA 高 30 倍。LPA 与其他脂质 GPCR 的结构比较表明，LPA 特征结合口袋中的负电荷允许对缺乏极性头部的 CpY 进行选择性识别。此外，我们的结构表明，CpY 的乙基基团直接推动 W271 以固定活性构象。内源性 LPA 缺乏这些化学特征，这代表了强力激活 LPA 的非脂类激动剂的关键要素。这项研究为非脂类激动剂对 LPA 的配体识别和激活提供了详细的机制见解，为针对 LPA 受体的药物开发扩展了范围。
