Structural mechanisms of potent lysophosphatidic acid receptor 1 activation by nonlipid basic agonists

Lysophosphatidic acid receptor 1 (LPA₁) is one of the G protein-coupled receptors activated by the lipid mediator, lysophosphatidic acid (LPA). LPA₁ is associated with a variety of diseases, and LPA₁ agonists have potential therapeutic value for treating obesity and depression. Although potent nonlipid LPA₁ agonists have recently been identified, the mechanisms of nonlipid molecule-mediated LPA₁ activation remain unclear. Here, we report a cryo-electron microscopy structure of the human LPA₁-G_i complex bound to a nonlipid basic agonist, CpY, which has 30-fold higher agonistic activity as compared with LPA. Structural comparisons of LPA₁ with other lipid GPCRs revealed that the negative charge in the characteristic binding pocket of LPA₁ allows the selective recognition of CpY, which lacks a polar head. In addition, our structure show that the ethyl group of CpY directly pushes W271^6.48 to fix the active conformation. Endogenous LPA lacks these chemical features, which thus represent the crucial elements of nonlipid agonists that potently activate LPA₁. This study provides detailed mechanistic insights into the ligand recognition and activation of LPA₁ by nonlipid agonists, expanding the scope for drug development targeting the LPA receptors.