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

Canrong Wu (), Youwei Xu, Qian He, Dianrong Li, Jia Duan, Changyao Li, Chongzhao You, Han Chen, Weiliang Fan, Yi Jiang and H. Eric Xu ()
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Canrong Wu: Chinese Academy of Sciences
Youwei Xu: Chinese Academy of Sciences
Qian He: Chinese Academy of Sciences
Dianrong Li: Sironax (Beijing) Co., Ltd.
Jia Duan: Chinese Academy of Sciences
Changyao Li: Lingang Laboratory
Chongzhao You: Chinese Academy of Sciences
Han Chen: Fujian Medical University
Weiliang Fan: Sironax (Beijing) Co., Ltd.
Yi Jiang: Lingang Laboratory
H. Eric Xu: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38411-x

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