9v81 | pdb_00009v81
cryoEM structure of HEP-50768-bound MRGPRX4-Gq complex
Structural highlights
FunctionGBB1_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.[1] Publication Abstract from PubMedChronic 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[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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