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Title | MRGPRX4 mediates phospho-drug-associated pruritus in a humanized mouse model. |
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Journal, issue, pages | Sci Transl Med, Vol. 16, Issue 746, Page eadk8198, Year 2024 |
Publish date | May 8, 2024 |
![]() | Daphne Chun-Che Chien / Nathachit Limjunyawong / Can Cao / James Meixiong / Qi Peng / Cheng-Ying Ho / Jonathan F Fay / Bryan L Roth / Xinzhong Dong / ![]() |
PubMed Abstract | The phosphate modification of drugs is a common chemical strategy to increase solubility and allow for parenteral administration. Unfortunately, phosphate modifications often elicit treatment- or ...The phosphate modification of drugs is a common chemical strategy to increase solubility and allow for parenteral administration. Unfortunately, phosphate modifications often elicit treatment- or dose-limiting pruritus through an unknown mechanism. Using unbiased high-throughput drug screens, we identified the Mas-related G protein-coupled receptor X4 (MRGPRX4), a primate-specific, sensory neuron receptor previously implicated in itch, as a potential target for phosphate-modified compounds. Using both G-mediated calcium mobilization and G protein-independent GPCR assays, we found that phosphate-modified compounds potently activate MRGPRX4. Furthermore, a humanized mouse model expressing MRGPRX4 in sensory neurons exhibited robust phosphomonoester prodrug-evoked itch. To characterize and confirm this interaction, we further determined the structure of MRGPRX4 in complex with a phosphate-modified drug through single-particle cryo-electron microscopy (cryo-EM) and identified critical amino acid residues responsible for the binding of the phosphate group. Together, these findings explain how phosphorylated drugs can elicit treatment-limiting itch and identify MRGPRX4 as a potential therapeutic target to suppress itch and to guide future drug design. |
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Methods | EM (single particle) |
Resolution | 3.14 Å |
Structure data | EMDB-39542, PDB-8yrg: |
Chemicals | ![]()
PDB-1lzu: CELLOBIOHYDROLASE CEL6A WILD TYPE WITH CELLOBIOIMIDAZOLE |
Source |
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