8YRG

CryoEM structure of fospropofol-bound MRGPRX4-Gq complex

これはPDB形式変換不可エントリーです。

8YRG の概要

• エントリーDOI: 10.2210/pdb8yrg/pdb
• EMDBエントリー: 39542
• 分子名称: 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)
• 機能のキーワード: gpcr-g protein complex, signaling protein
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 157717.28

構造登録者

Cao, C.,Fay, J.F.,Roth, B.L. (登録日: 2024-03-21, 公開日: 2024-05-22, 最終更新日: 2025-06-18)

主引用文献

Chien, D.C.,Limjunyawong, N.,Cao, C.,Meixiong, J.,Peng, Q.,Ho, C.Y.,Fay, J.F.,Roth, B.L.,Dong, X.
MRGPRX4 mediates phospho-drug-associated pruritus in a humanized mouse model.
Sci Transl Med, 16:eadk8198-eadk8198, 2024

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 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.

PubMed: 38718132
DOI: 10.1126/scitranslmed.adk8198

実験手法

ELECTRON MICROSCOPY (3.14 Å)