State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Sironax (Beijing) Co., Ltd., Beijing, 102206, China.
Nat Commun. 2023 May 9;14(1):2668. doi: 10.1038/s41467-023-38411-x.
Prostaglandin F (PGF), an endogenous arachidonic acid metabolite, regulates diverse physiological functions in many tissues and cell types through binding and activation of a G-protein-coupled receptor (GPCR), the PGF receptor (FP), which also is the primary therapeutic target for glaucoma and several other diseases. Here, we report cryo-electron microscopy (cryo-EM) structures of the human FP bound to endogenous ligand PGF and anti-glaucoma drugs LTPA and TFPA at global resolutions of 2.67 Å, 2.78 Å, and 3.14 Å. These structures reveal distinct features of FP within the lipid receptor family in terms of ligand binding selectivity, its receptor activation, and G protein coupling mechanisms, including activation in the absence of canonical PIF and ERY motifs and G coupling through direct interactions with receptor transmembrane helix 1 and intracellular loop 1. Together with mutagenesis and functional studies, our structures reveal mechanisms of ligand recognition, receptor activation, and G protein coupling by FP, which could facilitate rational design of FP-targeting drugs.
前列腺素 F（PGF）是一种内源性花生四烯酸代谢物，通过与 G 蛋白偶联受体（FP）结合和激活，调节许多组织和细胞类型的多种生理功能，FP 也是青光眼和其他几种疾病的主要治疗靶点。在这里，我们报告了与内源性配体 PGF 以及抗青光眼药物 LTPA 和 TFPA 结合的人 FP 的冷冻电镜（cryo-EM）结构，整体分辨率分别为 2.67Å、2.78Å 和 3.14Å。这些结构揭示了 FP 在脂质受体家族内的独特特征，包括配体结合选择性、受体激活和 G 蛋白偶联机制，包括在缺乏典型 PIF 和 ERY 基序的情况下的激活，以及通过与受体跨膜螺旋 1 和细胞内环 1 的直接相互作用进行 G 偶联。结合突变和功能研究，我们的结构揭示了 FP 识别配体、受体激活和 G 蛋白偶联的机制，这有助于 FP 靶向药物的合理设计。
