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Structural identification of lysophosphatidylcholines as activating ligands for orphan receptor GPR119

Abstract

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.

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Fig. 1: Identification of the LPC bound to GPR119–Gs complex by cryo-EM and mass spectrum.
Fig. 2: LPLs induce GPR119 activation.
Fig. 3: LPC-binding pocket of GPR119.
Fig. 4: Cryo-EM structure of the APD668-bound GPR119–Gs complex.
Fig. 5: Comparison of the LPC and APD668 binding modes.
Fig. 6: Gs coupling of GPR119.

Data availability

Materials are available from the corresponding authors upon reasonable request. Density maps and structure coordinates have been deposited in the Electron Microscopy Data Bank (EMDB) and the PDB with accession codes EMD-33525 and PDB 7XZ5 for the LPC-GPR119–Gs complex; EMD-33526 and PDB 7XZ6 for the APD668–GPR119–Gs complex. Source data are provided with this paper. All other relevant data are available from the corresponding author upon request.

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Acknowledgements

The cryo-EM data were collected at the Cryo-Electron Microscopy Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS) (Shanghai, China). This work was supported by the Ministry of Science and Technology (China) grant (2018YFA0507002 to H.E.X.); National Natural Science Foundation grants (32130022 to H.E.X., 82121005 to H.E.X., X.X. and Y.J., 81730099 to X.X., 32171187 to Y.J.); CAS Strategic Priority Research Program (XDB37030103 to H.E.X.); Shanghai Municipal Science and Technology Major Projects (2019SHZDZX02 to H.E.X. and TM202101H005 to X.X.), Shanghai Municipal Science and Technology Major Project (H.E.X.).

Author information

Authors and Affiliations

Authors

Contributions

P.X. and S.H. designed the expression constructs, purified the complexes, prepared samples for the cryo-EM as well as data collection and analysis. S.G., Y.Y. and Y.L. performed the functional assays and analyzed the data. X.C., X.H. and H.J. were responsible for the docking studies. P.C. and H.Z. were responsible for the mass spectrum studies. Y.J. participated in the supervision of P.X. and S.H., analyzed the structures and edited the manuscript. X.X. supervised the functional studies. H.E.X., X.X. and Y.J. conceived, designed and supervised the overall project. H.E.X., X.X., Y.J., P.X., S.H. and S.G. participated in data analysis and interpretation, and wrote the manuscript with inputs from all authors.

Corresponding authors

Correspondence to Yi Jiang, Xin Xie or H. Eric Xu.

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Extended data

Extended Data Fig. 1 Cryo-EM data processing of the LPC-GPR119-Gs-Nb35 structure.

a, Flowchart of cryo-EM data analysis of the LPC-GPR119-Gs-Nb35 complex. b, Representative cryo-EM image (scale bar, 50 nm) from 4,976 movies. c, Representative 2D averages show features of GPR119 TMD and Gs heterotrimer (scale bar, 5 nm). d, ‘Gold-standard’ Fourier shell correlation curves of the LPC- GPR119-Gs-Nb35 complex. e, Cryo-EM map and model of the LPC-GPR119-Gs-Nb35 complex. Cryo-EM density map and model are shown for all seven transmembrane α-helices from GPR119, LPC, Gαs α5 helices, and Gαs αN helices. Numerical data for graphs in b,c,d are available as source data.

Extended Data Fig. 2 Structural comparisons and functional data of the GPR119 activation by LPC.

a, Structural comparison of GPR119 with β2AR (PDB: 3SN6) and D1R (PDB: 7JVQ). b, Concentration-response of cAMP accumulation by the activation of GPR119 induced by LPC with different acyl tail. c, Mutagenesis data of LPC induced GPR119 activation. d, Relative expression of GPR119 mutants. Values are shown as the mean ± s.e.m. from at least three independent experiments performed in triplicate.

Source data

Extended Data Fig. 3 The unique TM5 structure of GPR119.

a-h, Structural comparisons of GPR119 with other class A GPCRs, including 5-HT1A (PDB: 7E2X), D1R (PDB: 7JVQ), CB1 (PDB: 6KPG), S1P1 (PDB: 7WF7), CLT1 (PDB: 6RZ4), BLT1 (PDB: 7K15), FFA1 (PDB: 5TZR), and LPA1 (PDB: 4Z34). i, The TM5 sequence alignment of GPR119 with other class A GPCRs shows a shift TM5 in GPR119 structure. The alignment was output from GPCRdb29 (gpcrdb.org) and edited based on the GPR119 structure.

Extended Data Fig. 4 Comparison of the orthosteric and allosteric (TM3-TM5-ICL3) pockets of GPR119 with other Class A GPCRs.

a, Structural comparison of the orthosteric ligand-binding pocket by GPR119 with other lipid-binding GPCRs, including CB1 (PDB: 6KPG), S1P1 (PDB: 7WF7), CLT1 (PDB: 6RZ4), BLT1 (PDB: 7K15), FFA1 (PDB: 5TZR), LPA1 (PDB: 4Z34), and PAFR (PDB: 5ZKP). b, Structural comparisons of the allosteric ligand-binding pocket (TM3-TM5-ICL3) by GPR119 with other class A GPCRs, including 5-HT1A (PDB: 7E2X), D1R (PDB: 7JVQ), CB1 (PDB: 6KPG), SIP1 (PDB: 7WF7), CLT1 (PDB: 6RZ4), BLT1 (PDB: 7K15), FFA1 (PDB: 5TZR), LPA1 (PDB: 4Z34). The allosteric binding pocket formed by TM3-TM5-ICL3 is circled with white dash lines.

Extended Data Fig. 5 Cryo-EM data processing of the APD668-GPR119-Gs-Nb35 structure.

a, Flowchart of cryo-EM data analysis of the APD668-GPR119-Gs-Nb35 complex. b, Representative cryo-EM image (scale bar, 50 nm) from 6,373 movies. c, Representative 2D averages show features of GPR119 TMD and Gs heterotrimer. d, ‘Gold-standard’ Fourier shell correlation curves of the APD668- GPR119-Gs-Nb35 complex. e, Cryo-EM map and model of the APD668-GPR119-Gs-Nb35 complex. Cryo-EM density map and model are shown for all seven transmembrane α-helices from GPR119, APD668, Gαs α5 helices, and Gαs αN helices.

Extended Data Fig. 6 Mutations increase the APD668 potency to GPR119.

a, d, g, cAMP assay shows mutations V85A (a), A89S (d), and A90S (g) increases the potency of APD668 to GPR119. Values are shown as the mean ± s.e.m. from at least three independent experiments performed in triplicate. b-c, the comparisons of the structure (b) and the V85A model (c) of APD668 bound-GPR119. e-f, the comparisons of the structure (e) and the A89S model (f) of APD668 bound-GPR119. h-i, the comparisons of the structure (h) and the A90S model (i) of APD668 bound-GPR119.

Extended Data Fig. 7 The activation of GPR119.

a-d, Structure of toggle switch residue W6.48 (a), PIF motif (b), DRY motif (c), and NPxxY motif (d) of GPR119 in compared with inactive and active β2AR, 5-HT1B, and D2R. e, The water molecule is coordinated by W2386.48, G2687.42, S2727.46, and N2717.45 of GPR119.

Extended Data Fig. 8 The unique interface of GPR119 ICL1 to the Gβ and Gαs subunits.

a-h, Structural comparisons at the ICL1 of GPR119-Gs with 5-HT1A-Gi, 5-HT1B-Gi, D1R-Gs, β2AR-Gs, CB1-Gi, and CB2-Gi complexes. i, Sequence alignment shows GPR119 has two more residues in the cytoplasmic end of the TM1 (1×61 and 1×62). The alignment was output from GPCRdb29 (gpcrdb.org) and edited based on the GPR119 structures.

Extended Data Fig. 9 Extended Data Fig.9 Docking and functional studies of fatty acid derivatives and a steroid glycoside Gordonoside F bind to GPR119.

a-d, Docking models of oleoylethanolamide (OEA, a), 2-oleoyl glycerol (2-OG, b), linoleylethanolamide (LEA, c), and 5-hydroxy-eicosapentaenoic acid (5-HEPE, d) to the GPR119 structure. e, Structure of Gordonoside F. f, The hydrophilic binding pocket is not favorable for Gordonoside F binding. g, The docking model of Gordonoside F binds to GPR119. h, Identification of the OEA-GPR119 recognition by cAMP assay. i, Identification of the Gordonoside F-GPR119 recognition by cAMP assay. Values are shown as the mean ± s.e.m. from at least three independent experiments performed in triplicate. UD indicates that the activation level is too low to determine EC50 values. Numerical data for graphs in h,i are available as source data.

Source data

Extended Data Fig. 10 Docking models of synthetic agonists to GPR119.

a, Comparison of the APD668-bound GPR119 structure with the docking models of 9 agonists to GPR119. b, The molecules used in docking studies and their docking scores.

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Xu, P., Huang, S., Guo, S. et al. Structural identification of lysophosphatidylcholines as activating ligands for orphan receptor GPR119. Nat Struct Mol Biol 29, 863–870 (2022). https://doi.org/10.1038/s41594-022-00816-5

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