FP receptor structures reveal the selectivity mechanism of prostaglandin

Abstract Prostaglandins and their receptors regulate various physiological processes, such as cardiovascular homeostasis, body temperature control and female production. Carboprost, an analog of prostaglandin F2α and an agonist for the prostaglandin F2-alpha receptor (FP receptor), is clinically used to treat postpartum hemorrhage (PPH), which is a leading cause of maternal morbidity and mortality. However, off-target activation of closely related receptors such as the EP3 receptor by carboprost results in side effects and limits the clinical application. Meanwhile, the FP receptor selective agonist latanoprost is not suitable to treat PPH due to its poor solubility and fast clearance. In this work, we determined two cryo-EM structures of the FP receptor bound to carboprost and latanoprost at 2.7 Å and 3.2 Å resolution, respectively. The structures reveal the molecular mechanism of FP receptor selectivity for both endogenous prostaglandins and clinical drugs, as well as the molecular mechanism of G protein coupling preference by the prostaglandin receptors. The structural information may guide the development of better prostaglandin drugs.