PDF(Pubmed)
Abstract：
Prostaglandins and their receptors regulate various physiological processes. 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). However, off-target activation of closely related receptors such as the prostaglandin E receptor subtype EP3 (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. Here, we present two cryo-EM structures of the FP receptor bound to carboprost and latanoprost-FA (the free acid form of 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.
摘要：
前列腺素及其受体调节各种生理过程。卡前列素,前列腺素F2α的类似物和前列腺素F2α受体（FP受体）的激动剂，临床上用于治疗产后出血（PPH）。然而,卡前列素对前列腺素E受体亚型EP3（EP3受体）等密切相关受体的脱靶激活会导致副作用，限制了临床应用。同时,FP受体选择性激动剂拉坦前列素由于其溶解性差和快速清除而不适合治疗PPH。这里,我们展示了与卡前列素和拉坦前列素-FA（拉坦前列素的游离酸形式）结合的FP受体的两种低温EM结构，分别。结构揭示了FP受体对内源性前列腺素和临床药物的选择性的分子机制，以及前列腺素受体对G蛋白偶联偏好的分子机制。结构信息可以指导更好的前列腺素药物的开发。
