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- EMDB-32133: Cryo-EM structure of pseudoallergen receptor MRGPRX2 complex with... -

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Basic information

Entry
Database: EMDB / ID: EMD-32133
TitleCryo-EM structure of pseudoallergen receptor MRGPRX2 complex with PAMP-12, local
Map dataCryo-EM structure of pseudoallergen receptor MRGPRX2 complex with PAMP-12, local
Sample
  • Complex: Cryo-EM structure of pseudoallergen receptor MRGPRX2 complex with PAMP-12, local
    • Protein or peptide: peptide from Pro-adrenomedullin
    • Protein or peptide: Mas-related G-protein coupled receptor member X2
  • Ligand: CHOLESTEROL
Function / homology
Function and homology information


adrenomedullin receptor binding / positive regulation of progesterone biosynthetic process / mast cell secretagogue receptor activity / vascular associated smooth muscle cell development / neuron projection regeneration / adrenomedullin receptor signaling pathway / mast cell activation / spongiotrophoblast layer development / Calcitonin-like ligand receptors / branching involved in labyrinthine layer morphogenesis ...adrenomedullin receptor binding / positive regulation of progesterone biosynthetic process / mast cell secretagogue receptor activity / vascular associated smooth muscle cell development / neuron projection regeneration / adrenomedullin receptor signaling pathway / mast cell activation / spongiotrophoblast layer development / Calcitonin-like ligand receptors / branching involved in labyrinthine layer morphogenesis / positive regulation of vasculogenesis / regulation of systemic arterial blood pressure / regulation of the force of heart contraction / neuropeptide binding / sleep / regulation of urine volume / G protein-coupled receptor internalization / negative regulation of vascular permeability / negative regulation of vasoconstriction / positive regulation of heart rate / mast cell degranulation / response to starvation / positive regulation of cytokinesis / odontogenesis of dentin-containing tooth / cAMP-mediated signaling / androgen metabolic process / developmental growth / vasculogenesis / animal organ regeneration / response to glucocorticoid / sensory perception of pain / neural tube closure / female pregnancy / G protein-coupled receptor activity / response to insulin / adenylate cyclase-activating G protein-coupled receptor signaling pathway / hormone activity / receptor internalization / positive regulation of angiogenesis / heart development / positive regulation of cytosolic calcium ion concentration / G alpha (s) signalling events / cell population proliferation / response to lipopolysaccharide / response to hypoxia / inflammatory response / positive regulation of apoptotic process / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / signaling receptor binding / positive regulation of cell population proliferation / signal transduction / extracellular space / extracellular region / membrane / plasma membrane / cytoplasm
Similarity search - Function
Pro-adrenomedullin / Mas-related G protein-coupled receptor family / Calcitonin/adrenomedullin / Calcitonin / CGRP / IAPP family / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
Pro-adrenomedullin / Mas-related G-protein coupled receptor member X2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLi Y / Yang F
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81773704, 92057121, 31900936, 31971195 China
CitationJournal: Nature / Year: 2021
Title: Structure, function and pharmacology of human itch receptor complexes.
Authors: Fan Yang / Lulu Guo / Yu Li / Guopeng Wang / Jia Wang / Chao Zhang / Guo-Xing Fang / Xu Chen / Lei Liu / Xu Yan / Qun Liu / Changxiu Qu / Yunfei Xu / Peng Xiao / Zhongliang Zhu / Zijian Li / ...Authors: Fan Yang / Lulu Guo / Yu Li / Guopeng Wang / Jia Wang / Chao Zhang / Guo-Xing Fang / Xu Chen / Lei Liu / Xu Yan / Qun Liu / Changxiu Qu / Yunfei Xu / Peng Xiao / Zhongliang Zhu / Zijian Li / Jiuyao Zhou / Xiao Yu / Ning Gao / Jin-Peng Sun /
Abstract: In the clades of animals that diverged from the bony fish, a group of Mas-related G-protein-coupled receptors (MRGPRs) evolved that have an active role in itch and allergic signals. As an MRGPR, ...In the clades of animals that diverged from the bony fish, a group of Mas-related G-protein-coupled receptors (MRGPRs) evolved that have an active role in itch and allergic signals. As an MRGPR, MRGPRX2 is known to sense basic secretagogues (agents that promote secretion) and is involved in itch signals and eliciting pseudoallergic reactions. MRGPRX2 has been targeted by drug development efforts to prevent the side effects induced by certain drugs or to treat allergic diseases. Here we report a set of cryo-electron microscopy structures of the MRGPRX2-G trimer in complex with polycationic compound 48/80 or with inflammatory peptides. The structures of the MRGPRX2-G complex exhibited shallow, solvent-exposed ligand-binding pockets. We identified key common structural features of MRGPRX2 and describe a consensus motif for peptidic allergens. Beneath the ligand-binding pocket, the unusual kink formation at transmembrane domain 6 (TM6) and the replacement of the general toggle switch from Trp to Gly (superscript annotations as per Ballesteros-Weinstein nomenclature) suggest a distinct activation process. We characterized the interfaces of MRGPRX2 and the G trimer, and mapped the residues associated with key single-nucleotide polymorphisms on both the ligand and G-protein interfaces of MRGPRX2. Collectively, our results provide a structural basis for the sensing of cationic allergens by MRGPRX2, potentially facilitating the rational design of therapies to prevent unwanted pseudoallergic reactions.
History
DepositionNov 4, 2021-
Header (metadata) releaseDec 1, 2021-
Map releaseDec 1, 2021-
UpdateJul 20, 2022-
Current statusJul 20, 2022Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.015
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  • Surface view with fitted model
  • Atomic models: PDB-7vv0
  • Surface level: 0.015
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_32133.png

Downloads & links

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Map

FileDownload / File: emd_32133.map.gz / Format: CCP4 / Size: 31.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of pseudoallergen receptor MRGPRX2 complex with PAMP-12, local
Voxel sizeX=Y=Z: 0.8286 Å
Density
Contour LevelBy AUTHOR: 0.012 / Movie #1: 0.015
Minimum - Maximum-0.13101184 - 0.170455
Average (Standard dev.)8.2225975e-05 (±0.0029441407)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions202202202
Spacing202202202
CellA=B=C: 167.3772 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.828599009900990.828599009900990.82859900990099
M x/y/z202202202
origin x/y/z0.0000.0000.000
length x/y/z167.377167.377167.377
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS202202202
D min/max/mean-0.1310.1700.000

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Supplemental data

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Sample components

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Entire : Cryo-EM structure of pseudoallergen receptor MRGPRX2 complex with...

EntireName: Cryo-EM structure of pseudoallergen receptor MRGPRX2 complex with PAMP-12, local
Components
  • Complex: Cryo-EM structure of pseudoallergen receptor MRGPRX2 complex with PAMP-12, local
    • Protein or peptide: peptide from Pro-adrenomedullin
    • Protein or peptide: Mas-related G-protein coupled receptor member X2
  • Ligand: CHOLESTEROL

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Supramolecule #1: Cryo-EM structure of pseudoallergen receptor MRGPRX2 complex with...

SupramoleculeName: Cryo-EM structure of pseudoallergen receptor MRGPRX2 complex with PAMP-12, local
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: peptide from Pro-adrenomedullin

MacromoleculeName: peptide from Pro-adrenomedullin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.624952 KDa
SequenceString:
FRKKWNKWAL SR

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Macromolecule #2: Mas-related G-protein coupled receptor member X2

MacromoleculeName: Mas-related G-protein coupled receptor member X2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.123984 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDPTTPAWGT ESTTVNGNDQ ALLLLCGKET LIPVFLILFI ALVGLVGNGF VLWLLGFRMR RNAFSVYVLS LAGADFLFLC FQIINCLVY LSNFFCSISI NFPSFFTTVM TCAYLAGLSM LSTVSTERCL SVLWPIWYRC RRPRHLSAVV CVLLWALSLL L SILEGKFC ...String:
MDPTTPAWGT ESTTVNGNDQ ALLLLCGKET LIPVFLILFI ALVGLVGNGF VLWLLGFRMR RNAFSVYVLS LAGADFLFLC FQIINCLVY LSNFFCSISI NFPSFFTTVM TCAYLAGLSM LSTVSTERCL SVLWPIWYRC RRPRHLSAVV CVLLWALSLL L SILEGKFC GFLFSDGDSG WCQTFDFITA AWLIFLFMVL CGSSLALLVR ILCGSRGLPL TRLYLTILLT VLVFLLCGLP FG IQWFLIL WIWKDSDVLF CHIHPVSVVL SSLNSSANPI IYFFVGSFRK QWRLQQPILK LALQRALQDI AEVDHSEGCF RQG TPEMSR SSLV

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 58.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 978001

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