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- Title
Structural basis for ligand recognition and signaling of the lysophosphatidylserine receptors GPR34 and GPR174.
- Authors
Liu, Guibing; Li, Xiu; Wang, Yujing; Zhang, Xuan; Gong, Weimin
- Abstract
Lysophosphatidylserine (LysoPS) is a naturally occurring lipid mediator involved in various physiological and pathological processes especially those related to the immune system. GPR34, GPR174, and P2Y10 have been identified as the receptors for LysoPS, and its analogues have been developed as agonists or antagonists for these receptors. However, the lack of structural information hinders the drug development with novel characteristics, such as nonlipid ligands and allosteric modulators. Here, we determined the structures of human GPR34 and GPR174 in complex with LysoPS and G protein by cryo-EM. Combined with structural analysis and functional studies, we elucidated the lipid-binding modes of these receptors. By structural comparison, we identified the structural features of GPR34 and GPR174 in active state. Taken together, our findings provide insights into ligand recognition and signaling of LysoPS receptors and will facilitate the development of novel therapeutics for related inflammatory diseases and autoimmune diseases. Lysophosphatidylserine (LysoPS) is a lipid signalling molecule implicated in a range of processes related to the immune system. This structural study reveals the mechanism of LysoPS recognition by two G protein-coupled receptors, GPR34 and GPR174, offering insights into lysophospholipid signaling and presenting opportunities for drug discovery.
- Subjects
G protein coupled receptors; DRUG discovery; G proteins; AUTOIMMUNE diseases; IMMUNE system; DRUG development
- Publication
PLoS Biology, 2023, Vol 21, Issue 12, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3002387