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Cryo-EM structure of the PGF2-alpha-bound human PTGFR-Gq complex
Structural highlights
FunctionGBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.[1] Publication Abstract from PubMedProstaglandin F(2alpha) (PGF(2alpha)), 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(2alpha) 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(2alpha) and anti-glaucoma drugs LTPA and TFPA at global resolutions of 2.67 A, 2.78 A, and 3.14 A. 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(q) 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. Ligand-induced activation and G protein coupling of prostaglandin F(2alpha) receptor.,Wu C, Xu Y, He Q, Li D, Duan J, Li C, You C, Chen H, Fan W, Jiang Y, Eric Xu H Nat Commun. 2023 May 9;14(1):2668. doi: 10.1038/s41467-023-38411-x. PMID:37160891[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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