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TitleStructural identification of lysophosphatidylcholines as activating ligands for orphan receptor GPR119.
Journal, issue, pagesNat Struct Mol Biol, Vol. 29, Issue 9, Page 863-870, Year 2022
Publish dateAug 15, 2022
AuthorsPeiyu Xu / Sijie Huang / Shimeng Guo / Ying Yun / Xi Cheng / Xinheng He / Pengjun Cai / Yuan Lan / Hu Zhou / Hualiang Jiang / Yi Jiang / Xin Xie / H Eric Xu /
PubMed AbstractLysophosphatidylcholine (LPC) is an essential mediator in human lipid metabolism and is associated with a variety of diseases, but the exact identity of LPC receptors remains controversial. Through ...Lysophosphatidylcholine (LPC) is an essential mediator in human lipid metabolism and is associated with a variety of diseases, but the exact identity of LPC receptors remains controversial. Through extensive biochemical and structural analyses, we have identified the orphan receptor GPR119 as the receptor for LPC. The structure of the GPR119-G-protein complex without any added ligands reveals a density map that fits well with LPC, which is further confirmed by mass spectrometry and functional studies. As LPCs are abundant on the cell membrane, their preoccupancy in the receptor may lead to 'constitutive activity' of GPR119. The structure of GPR119 bound to APD668, a clinical drug candidate for type 2 diabetes, reveals an exceedingly similar binding mode to LPC. Together, these data highlight structural evidence for LPC function in regulating glucose-dependent insulin secretion through direct binding and activation of GPR119, and provide structural templates for drug design targeting GPR119.
External linksNat Struct Mol Biol / PubMed:35970999
MethodsEM (single particle)
Resolution2.8 - 3.1 Å
Structure data

EMDB-33525, PDB-7xz5:
GPR119-Gs-LPC complex
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-33526, PDB-7xz6:
GPR119-Gs-APD668 complex
Method: EM (single particle) / Resolution: 2.8 Å

Chemicals

ChemComp-LSC:
(4R,7R,18E)-4,7-dihydroxy-N,N,N-trimethyl-10-oxo-3,5,9-trioxa-4-phosphaheptacos-18-en-1-aminium 4-oxide

ChemComp-I7J:
propan-2-yl 4-[1-(2-fluoranyl-4-methylsulfonyl-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]oxypiperidine-1-carboxylate

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • lama glama (llama)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / GPCR / Glucose-dependent insulinotropic receptor / GPR119 / LysoPC / Lysophosphatidylcholine / G-protein / Gs / signaling complex / structure-function relationships / APD668 / cryo-EM structure

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