7XZ6

GPR119-Gs-APD668 complex

Summary for 7XZ6

• Entry DOI: 10.2210/pdb7xz6/pdb
• EMDB information: 33526
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: gpcr, glucose-dependent insulinotropic receptor, gpr119, lysopc, lysophosphatidylcholine, apd668, g-protein, gs, signaling complex, cryo-em structure, structure-function relationships, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 161010.65

Authors

Xu, P.,Huang, S.,Jiang, Y.,Xu, H.E. (deposition date: 2022-06-02, release date: 2022-08-24, Last modification date: 2024-11-20)

Primary citation

Xu, P.,Huang, S.,Guo, S.,Yun, Y.,Cheng, X.,He, X.,Cai, P.,Lan, Y.,Zhou, H.,Jiang, H.,Jiang, Y.,Xie, X.,Xu, H.E.
Structural identification of lysophosphatidylcholines as activating ligands for orphan receptor GPR119.
Nat.Struct.Mol.Biol., 29:863-870, 2022

PubMed 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.

PubMed: 35970999
DOI: 10.1038/s41594-022-00816-5

Experimental method

ELECTRON MICROSCOPY (2.8 Å)