9V81

cryoEM structure of HEP-50768-bound MRGPRX4-Gq complex

This is a non-PDB format compatible entry.

Summary for 9V81

• Entry DOI: 10.2210/pdb9v81/pdb
• EMDB information: 64829
• Descriptor: Gs-mini-Gq chimera, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: signal transduction, membrane protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 5
• Total formula weight: 157779.27

Authors

Wang, C.,Zhang, M.,Cao, C. (deposition date: 2025-05-29, release date: 2026-05-06)

Primary citation

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.
Development of a clinically viable MRGPRX4 inverse agonist for cholestatic itch treatment.
Nat.Chem.Biol., 2026

PubMed Abstract: 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.

PubMed: 41957282
DOI: 10.1038/s41589-026-02195-0

Experimental method

ELECTRON MICROSCOPY (2.63 Å)