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

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Basic information

Entry
Database: PDB / ID: 7vdm
TitleCryo-EM structure of pseudoallergen receptor MRGPRX2 complex with substance P
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Mas-related G-protein coupled receptor member X2
  • peptide from Protachykinin-1
  • scFv
KeywordsMEMBRANE PROTEIN / G Protein-Coupled Receptor
Function / homology
Function and homology information


substance P receptor binding / positive regulation of corticosterone secretion / mast cell secretagogue receptor activity / Tachykinin receptors bind tachykinins / insemination / positive regulation of synaptic transmission, cholinergic / detection of abiotic stimulus / mast cell activation / positive regulation of lymphocyte proliferation / tachykinin receptor signaling pathway ...substance P receptor binding / positive regulation of corticosterone secretion / mast cell secretagogue receptor activity / Tachykinin receptors bind tachykinins / insemination / positive regulation of synaptic transmission, cholinergic / detection of abiotic stimulus / mast cell activation / positive regulation of lymphocyte proliferation / tachykinin receptor signaling pathway / positive regulation of action potential / positive regulation of acute inflammatory response / sleep / positive regulation of ossification / neuropeptide binding / negative regulation of heart rate / response to pain / mast cell degranulation / positive regulation of cytokinesis / neuronal dense core vesicle / associative learning / positive regulation of epithelial cell migration / neuropeptide signaling pathway / long-term memory / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway / response to hormone / D2 dopamine receptor binding / response to prostaglandin E / positive regulation of stress fiber assembly / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / sensory perception of pain / cellular response to forskolin / regulation of mitotic spindle organization / positive regulation of synaptic transmission, GABAergic / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / negative regulation of insulin secretion / cellular response to nerve growth factor stimulus / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to peptide hormone / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / regulation of blood pressure / centriolar satellite / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / cell-cell signaling / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / G protein activity / positive regulation of cytosolic calcium ion concentration / GTPase binding / Ca2+ pathway / midbody / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / cell cortex
Similarity search - Function
Tachykinin family / Tachykinin family / Tachykinin domain / Tachykinin family / Tachykinin/Neurokinin-like, conserved site / Tachykinin family signature. / Mas-related G protein-coupled receptor family / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller ...Tachykinin family / Tachykinin family / Tachykinin domain / Tachykinin family / Tachykinin/Neurokinin-like, conserved site / Tachykinin family signature. / Mas-related G protein-coupled receptor family / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
CHOLESTEROL / Protachykinin-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Mas-related G-protein coupled receptor member X2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.98 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
DepositionSep 7, 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 1.2Nov 20, 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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Structure visualization

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
S: scFv
R: Mas-related G-protein coupled receptor member X2
L: peptide from Protachykinin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)155,4337
Polymers155,0466
Non-polymers3871
Water00
1


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

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40415.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39418.086 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 6375.332 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody / Protein / Protein/peptide / Non-polymers , 4 types, 4 molecules SRL

#4: Antibody scFv


Mass: 30363.043 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#5: 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
#6: Protein/peptide peptide from Protachykinin-1 / substance P


Mass: 1350.629 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TAC1, NKA, NKNA, TAC2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P20366
#7: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O

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Details

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: The pseudoallergen receptor MRGPRX2 complex with substance P
Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
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: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 636987 / Symmetry type: POINT

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