7xz6
GPR119-Gs-APD668 complex
Structural highlights
FunctionGBG2_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). Publication Abstract from PubMedLysophosphatidylcholine (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. Structural identification of lysophosphatidylcholines as activating ligands for orphan receptor GPR119.,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 HE Nat Struct Mol Biol. 2022 Sep;29(9):863-870. doi: 10.1038/s41594-022-00816-5. , Epub 2022 Aug 15. PMID:35970999[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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