8YRG
CryoEM structure of fospropofol-bound MRGPRX4-Gq complex
This is a non-PDB format compatible entry.
Summary for 8YRG
| Entry DOI | 10.2210/pdb8yrg/pdb |
| EMDB information | 39542 |
| Descriptor | 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) |
| Functional Keywords | gpcr-g protein complex, signaling protein |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 5 |
| Total formula weight | 157717.28 |
| Authors | Cao, C.,Fay, J.F.,Roth, B.L. (deposition date: 2024-03-21, release date: 2024-05-22, Last modification date: 2025-06-18) |
| Primary citation | 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 Cited by 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: 38718132DOI: 10.1126/scitranslmed.adk8198 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.14 Å) |
Structure validation
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