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TitleLigand-induced activation and G protein coupling of prostaglandin F receptor.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 2668, Year 2023
Publish dateMay 9, 2023
AuthorsCanrong Wu / Youwei Xu / Qian He / Dianrong Li / Jia Duan / Changyao Li / Chongzhao You / Han Chen / Weiliang Fan / Yi Jiang / H Eric Xu /
PubMed AbstractProstaglandin 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 ...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.
External linksNat Commun / PubMed:37160891 / PubMed Central
MethodsEM (single particle)
Resolution2.67 - 3.14 Å
Structure data

EMDB-35724, PDB-8iuk:
Cryo-EM structure of the PGF2-alpha-bound human PTGFR-Gq complex
Method: EM (single particle) / Resolution: 2.67 Å

EMDB-35725, PDB-8iul:
Cryo-EM structure of the latanoprost-bound human PTGFR-Gq complex
Method: EM (single particle) / Resolution: 2.78 Å

EMDB-35726, PDB-8ium:
Cryo-EM structure of the tafluprost acid-bound human PTGFR-Gq complex
Method: EM (single particle) / Resolution: 3.14 Å

Chemicals

ChemComp-UGU:
(Z)-7-[(1R,2R,3R,5S)-3,5-bis(oxidanyl)-2-[(E,3S)-3-oxidanyloct-1-enyl]cyclopentyl]hept-5-enoic acid

ChemComp-7WT:
Z-7-[(1R,2R,3R,5S)-3,5-bis(oxidanyl)-2-[(3R)-3-oxidanyl-5-phenyl-pentyl]cyclopentyl]hept-5-enoic acid

ChemComp-S2F:
(~{Z})-7-[(1~{R},2~{R},3~{R},5~{S})-2-[(~{E})-3,3-bis(fluoranyl)-4-phenoxy-but-1-enyl]-3,5-bis(oxidanyl)cyclopentyl]hept-5-enoic acid

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • lama glama (llama)
KeywordsMEMBRANE PROTEIN / GPCR / PTGFR / PGF2-alpha / Gq / Latanoprost / TFPA

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