Cell Discovery, 13 May, 2025, DOI：http://dx.doi.org/10.1038/s41421-025-00799-9

Structural insights into ligand recognition and activation of human purinergic receptor P2Y14

Quanchang Gu, Zhenyu Lv, Tianxin Wang, Wenqin Tang, Xuzhen Guo, Xiangling Huang, Fahui Li & Jiangyun Wang

Abstract

Purinergic receptors, including P2Y1-like receptors (P2Y1, 2, 4, 6, and 11) that signal through G_q/11 proteins and P2Y12-like receptors (P2Y12, 13, and 14) that activate G_i/o proteins, are involved in diverse physiological processes such as cell proliferation, chemotaxis, inflammation, cancer metastasis, cardiovascular events, neurodegenerative diseases, and aging. To date, active and inactive structures of P2Y1 and P2Y12 have been resolved, providing structural insights into P2Y receptor signaling mechanisms. UDP-sugars, including UDP-glucose (UDPG), UDP-glucuronic acid (UDPGA), UDP-galactose, and UDP-N-acetylglucosamine, are produced in the cytoplasmic matrix under normal physiological conditions and play important roles in regulating blood sugar levels, fat metabolism, and inflammation. UDP-sugars are secreted into the extracellular space to function as the paracrine signals through the G-protein-coupled purinergic receptor, P2Y14, which senses extracellular metabolic stress signals and regulates energy homeostasis. P2Y14 couples to Gi signaling pathways, orchestrating a wide range of biological processes ranging from gastric function to immune responses, renal inflammation, and liver fibrosis. Therefore, P2Y14 has emerged as a promising therapeutic target for asthma, acute kidney injury, and inflammatory bowel disease (IBD) (Fig. 1a). Despite its significance, the molecular activation mechanism underlying its ability to recognize diverse ligands and couple G_i protein remains elusive. There is an urgent need to delineate the molecular mechanism underlying P2Y14 signaling.

Article link：https://www.nature.com/articles/s41421-025-00799-9