9V82Summary for 9V82
| Entry DOI | 10.2210/pdb9v82/pdb |
| EMDB information | 64830 |
| Descriptor | Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4, 5-[2-fluoranyl-3-[(2S)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]phenyl]-1H-1,2,3,4-tetrazole (2 entities in total) |
| Functional Keywords | g protein-coupled receptor, signaling protein |
| Biological source | Escherichia coli More |
| Total number of polymer chains | 1 |
| Total formula weight | 53746.29 |
| Authors | |
| 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 Cited by 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: 41957282DOI: 10.1038/s41589-026-02195-0 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.56 Å) |
Structure validation
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