8yrg
From Proteopedia
CryoEM structure of fospropofol-bound MRGPRX4-Gq complex
Structural highlights
Publication Abstract from PubMedThe 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(q)-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. MRGPRX4 mediates phospho-drug-associated pruritus in a humanized mouse model.,Chien DC, Limjunyawong N, Cao C, Meixiong J, Peng Q, Ho CY, Fay JF, Roth BL, Dong X Sci Transl Med. 2024 May 8;16(746):eadk8198. doi: 10.1126/scitranslmed.adk8198. , Epub 2024 May 8. PMID:38718132[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Mus musculus | Cao C | Fay JF | Roth BL