9v82 | pdb_00009v82

Local refine map of HEP-50768-bound MRGPRX4

spinqualitylabelsall models 9v82, resolution 2.56Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9v82 is a 1 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.56Å Ligands: A1L9Y Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function C562_ECOLX Electron-transport protein of unknown function.MRGX4_HUMAN Orphan receptor. Probably involved in the function of nociceptive neurons. May regulate nociceptor function and/or development, including the sensation or modulation of pain. Potently activated by enkephalins (By similarity). Publication Abstract from PubMed Chronic itch, particularly in cholestatic and uremic conditions, poses a notable clinical burden, yet treatment options remain inadequate. MRGPRX4 (hX4), a bile-acid-sensing G-protein-coupled receptor predominantly expressed in human sensory neurons, has emerged as a critical mediator of cholestatic pruritus. Here we identified and characterized HEP-50768, a potent and selective small-molecule inverse agonist of hX4 through high-throughput screening and structure-activity optimization. Structural elucidation through cryo-electron microscopy of the hX4-inverse agonist complex structure revealed the unique binding mode and inhibitory mechanism of HEP-50768. In hX4-humanized rats, HEP-50768 robustly suppressed bile-acid-induced pruritic behaviors. Comprehensive preclinical absorption, distribution, metabolism, excretion and safety profiling was performed in both rats and monkeys, and these findings establish HEP-50768 as a promising therapeutic candidate for chronic itch, supporting its advancement to clinical evaluation. Development of a clinically viable MRGPRX4 inverse agonist for cholestatic itch treatment.,Yang J, Shen R, Wang C, Zhu W, Ke H, Fan J, Zhang M, Liu Y, Li S, Li G, Wang X, Li Y, Cao C, Lei X Nat Chem Biol. 2026 Apr 9. doi: 10.1038/s41589-026-02195-0. PMID:41957282 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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