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TitleStructures of human prostaglandin F receptor reveal the mechanism of ligand and G protein selectivity.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 8136, Year 2023
Publish dateDec 8, 2023
AuthorsXiuqing Lv / Kaixuan Gao / Jia Nie / Xin Zhang / Shuhao Zhang / Yinhang Ren / Xiaoou Sun / Qi Li / Jingrui Huang / Lijuan Liu / Xiaowen Zhang / Weishe Zhang / Xiangyu Liu /
PubMed AbstractProstaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F and an agonist for the prostaglandin F2-alpha receptor (FP receptor), is ...Prostaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F and an agonist for the prostaglandin F2-alpha receptor (FP receptor), is clinically used to treat postpartum hemorrhage (PPH). However, off-target activation of closely related receptors such as the prostaglandin E receptor subtype EP3 (EP3 receptor) by carboprost results in side effects and limits the clinical application. Meanwhile, the FP receptor selective agonist latanoprost is not suitable to treat PPH due to its poor solubility and fast clearance. Here, we present two cryo-EM structures of the FP receptor bound to carboprost and latanoprost-FA (the free acid form of latanoprost) at 2.7 Å and 3.2 Å resolution, respectively. The structures reveal the molecular mechanism of FP receptor selectivity for both endogenous prostaglandins and clinical drugs, as well as the molecular mechanism of G protein coupling preference by the prostaglandin receptors. The structural information may guide the development of better prostaglandin drugs.
External linksNat Commun / PubMed:38065938 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.4 Å
Structure data

35657

8iq4

EMDB-35657, PDB-8iq4:
Cryo-EM structure of Carboprost-bound prostaglandin-F2-alpha receptor-miniGq-Nb35 complex
Method: EM (single particle) / Resolution: 2.7 Å

35658

8iq6

EMDB-35658, PDB-8iq6:
Cryo-EM structure of Latanoprost-bound prostaglandin-F2-alpha receptor-miniGq-Nb35 complex
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-87Q:
Z-7-[(1R,2R,3R,5S)-2-[(E,3S)-3-methyl-3-oxidanyl-oct-1-enyl]-3,5-bis(oxidanyl)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

Source
  • homo sapiens (human)
  • vicugna pacos (alpaca)
KeywordsMEMBRANE PROTEIN / GPCR / Complex / Prostaglandin receptor / Agonist

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