+
Open data
-
Basic information
Entry | Database: PDB / ID: 8yrg | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | CryoEM structure of fospropofol-bound MRGPRX4-Gq complex | |||||||||
![]() |
| |||||||||
![]() | ![]() | |||||||||
Function / homology | ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | |||||||||
Method | ![]() ![]() ![]() | |||||||||
![]() | Cao, C. / Fay, J.F. / Roth, B.L. | |||||||||
Funding support | ![]()
| |||||||||
![]() | ![]() Title: MRGPRX4 mediates phospho-drug-associated pruritus in a humanized mouse model. Authors: Daphne Chun-Che Chien / Nathachit Limjunyawong / Can Cao / James Meixiong / Qi Peng / Cheng-Ying Ho / Jonathan F Fay / Bryan L Roth / Xinzhong Dong / ![]() 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. | |||||||||
History |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 202.9 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
---|
-Related structure data
Related structure data | ![]() 39542MC M: map data used to model this data C: citing same article ( |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
-
Assembly
Deposited unit | ![]()
|
---|---|
1 |
|
-
Components
-Protein , 2 types, 2 molecules BR
#1: Protein | Mass: 28084.832 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
---|---|
#5: Protein | Mass: 53396.020 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
-Guanine nucleotide-binding protein ... , 2 types, 2 molecules CD
#2: Protein | Mass: 39418.086 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
---|---|
#3: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
-Antibody / Non-polymers , 2 types, 2 molecules E
#4: Antibody | Mass: 28668.922 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() ![]() |
---|---|
#6: Chemical | ChemComp-A1LZU / [ Mass: 288.277 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H21O5P / Feature type: SUBJECT OF INVESTIGATION |
-Details
Has ligand of interest | Y |
---|
-Experimental details
-Experiment
Experiment | Method: ![]() |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: ![]() |
-
Sample preparation
Component | Name: fospropofol-bound MRGPRX4-Gq complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT |
---|---|
Molecular weight | Value: 150 kDa/nm / Experimental value: NO |
Source (natural) | Organism: ![]() ![]() |
Source (recombinant) | Organism: ![]() ![]() ![]() |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied![]() ![]() |
Vitrification![]() | Cryogen name: ETHANE-PROPANE / Humidity: 100 % |
-
Electron microscopy imaging
Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |
---|---|
Microscopy | Model: FEI TALOS ARCTICA |
Electron gun | Electron source![]() ![]() |
Electron lens | Mode: BRIGHT FIELD![]() |
Image recording | Electron dose: 56.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-
Processing
CTF correction![]() | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
---|---|
3D reconstruction![]() | Resolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 375325 / Symmetry type: POINT |