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- PDB-7vv0: Cryo-EM structure of pseudoallergen receptor MRGPRX2 complex with... -

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Basic information

Entry
Database: PDB / ID: 7vv0
TitleCryo-EM structure of pseudoallergen receptor MRGPRX2 complex with PAMP-12, local
Components
  • Mas-related G-protein coupled receptor member X2
  • peptide from Pro-adrenomedullin
KeywordsMEMBRANE PROTEIN / G Protein-Coupled Receptor
Function / homology
Function and homology information


adrenomedullin receptor binding / positive regulation of progesterone biosynthetic process / mast cell secretagogue receptor activity / neuron projection regeneration / vascular associated smooth muscle cell development / adrenomedullin receptor signaling pathway / mast cell activation / branching involved in labyrinthine layer morphogenesis / regulation of systemic arterial blood pressure / positive regulation of vasculogenesis ...adrenomedullin receptor binding / positive regulation of progesterone biosynthetic process / mast cell secretagogue receptor activity / neuron projection regeneration / vascular associated smooth muscle cell development / adrenomedullin receptor signaling pathway / mast cell activation / branching involved in labyrinthine layer morphogenesis / regulation of systemic arterial blood pressure / positive regulation of vasculogenesis / Calcitonin-like ligand receptors / response to ether / regulation of the force of heart contraction / regulation of urine volume / G protein-coupled receptor internalization / neuropeptide binding / sleep / negative regulation of vascular permeability / negative regulation of vasoconstriction / mast cell degranulation / response to starvation / positive regulation of cytokinesis / odontogenesis of dentin-containing tooth / androgen metabolic process / developmental growth / animal organ regeneration / vasculogenesis / positive regulation of heart rate / response to glucocorticoid / sensory perception of pain / female pregnancy / response to insulin / neural tube closure / G protein-coupled receptor activity / hormone activity / receptor internalization / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of angiogenesis / cellular response to xenobiotic stimulus / heart development / positive regulation of cytosolic calcium ion concentration / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / secretory granule lumen / G alpha (s) signalling events / response to lipopolysaccharide / response to hypoxia / cell population proliferation / G protein-coupled receptor signaling pathway / positive regulation of apoptotic process / inflammatory response / signaling receptor binding / negative regulation of cell population proliferation / 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
CHOLESTEROL / Pro-adrenomedullin / Mas-related G-protein coupled receptor member X2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLi, Y. / Yang, F.
Funding support China, 1items
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, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 1, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 20, 2022Group: Database references / Structure summary / Category: audit_author / citation / citation_author
Item: _audit_author.name / _citation.country ..._audit_author.name / _citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Assembly

Deposited unit
L: peptide from Pro-adrenomedullin
R: Mas-related G-protein coupled receptor member X2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,1363
Polymers38,7492
Non-polymers3871
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein/peptide peptide from Pro-adrenomedullin / PAMP12


Mass: 1624.952 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P35318
#2: Protein Mas-related G-protein coupled receptor member X2


Mass: 37123.984 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MRGPRX2, MRGX2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96LB1
#3: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cryo-EM structure of pseudoallergen receptor MRGPRX2 complex with PAMP-12, local
Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 58 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 978001 / Symmetry type: POINT

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