Ligand-induced activation and G protein coupling of prostaglandin F2α receptor

Author(s): Canrong Wu (1), Youwei Xu (2), Qian He (2), Dianrong Li (3), Jia Duan (2), Changyao Li (4,5), Chongzhao You (2), Han Chen (6), Weiliang Fan (3), Yi Jiang (4,5), H Eric Xu (7,8)

1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. wucanrong@simm.ac.cn.
2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
3 Sironax (Beijing) Co., Ltd., Beijing, 102206, China.
4 Lingang Laboratory, Shanghai, 200031, China.
5 School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China.
6 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350108, China.
7 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. eric.xu@simm.ac.cn.
8 University of Chinese Academy of Sciences, Beijing, 100049, China. eric.xu@simm.ac.cn.

Prostaglandin F2α (PGF2α), 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 PGF2α 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 PGF2α 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 Gq 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.

Nat Commun. 2023 May 9;14(1):2668. doi: 10.1038/s41467-023-38411-x.

PMID: 37160891 PMCID: PMC10169810 DOI: 10.1038/s41467-023-38411-x

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