23CY

Cryo-EM structure of the MRGPRX4-miniGsq complex bound to the inverse agonist cmpd54-4, local

This is a non-PDB format compatible entry.

Summary for 23CY

• Entry DOI: 10.2210/pdb23cy/pdb
• EMDB information: 68874
• Descriptor: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4, (2~{S})-2-[[3-[[2-chloranyl-4-(trifluoromethyl)phenoxy]methyl]phenyl]carbonylamino]propanoic acid (2 entities in total)
• Functional Keywords: membrane protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 1
• Total formula weight: 53797.78

Authors

Cao, C.,Wang, C.,Zhang, M.,Ji, Z. (deposition date: 2026-02-01, release date: 2026-10-14, Last modification date: 2026-11-04)

Primary citation

Zhang, M.,Wang, Y.,Huang, Y.,Liang, Y.,Chen, P.,Ji, Z.,Song, M.,Chen, H.,Wang, C.,Cao, C.
Structural insights into the ligand modulation of MRGPRX4 conformational plasticity.
Cell Discov, 12:-, 2026

PubMed Abstract: Chronic pruritus is a debilitating condition with limited treatment options, particularly in cholestatic liver diseases, where bile acid dysregulation is a known trigger. Although Mas-related G protein-coupled receptor X4 (MRGPRX4) has recently been identified as a key mediator of bile acid-induced pruritus, the structural mechanisms underlying its inhibition remain poorly understood, hindering the development of therapeutic antagonists. Here, we report the cryo-electron microscopy structures of MRGPRX4 in three distinct states: agonist-bound state, antagonist-bound state, and apo state. Our structures reveal a previously unrecognized antagonist-binding site that is structurally distinct from those engaged by agonists. Complementary functional assays and molecular dynamics simulations further demonstrate that the extracellular pocket of MRGPRX4 undergoes pronounced ligand-dependent conformational rearrangements upon binding to both the agonist and the antagonist. Collectively, these findings elucidate the conformational plasticity underlying MRGPRX4 activity modulation and establish a structural framework for the rational design of MRGPRX4 antagonists that target chronic pruritus.

PubMed: 42869878
DOI: 10.1038/s41421-026-00929-x

Experimental method

ELECTRON MICROSCOPY (2.84 Å)