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- EMDB-36233: CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22 -

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Entry
Database: EMDB / ID: EMD-36233
TitleCryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22
Map data
Sample
  • Complex: CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: BAM8-22
    • Protein or peptide: Single-Chain Fragment Variable 16
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Mas-related G-protein coupled receptor member X1
Keywordsitch receptor / Mas-related GPCRs / MRGPRX1 / STRUCTURAL PROTEIN
Function / homology
Function and homology information


synaptic vesicle lumen / neuronal dense core vesicle lumen / response to chloroquine / chromaffin granule lumen / opioid receptor binding / opioid peptide activity / synaptic signaling via neuropeptide / general adaptation syndrome, behavioral process / aggressive behavior / positive regulation of behavioral fear response ...synaptic vesicle lumen / neuronal dense core vesicle lumen / response to chloroquine / chromaffin granule lumen / opioid receptor binding / opioid peptide activity / synaptic signaling via neuropeptide / general adaptation syndrome, behavioral process / aggressive behavior / positive regulation of behavioral fear response / G protein-coupled opioid receptor signaling pathway / symmetric synapse / cell body fiber / response to epinephrine / sensory perception / cellular response to vitamin D / neuropeptide hormone activity / startle response / transmission of nerve impulse / locomotory exploration behavior / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / neuropeptide signaling pathway / regulation of cAMP-mediated signaling / behavioral fear response / D2 dopamine receptor binding / glial cell proliferation / G protein-coupled serotonin receptor binding / axon terminus / regulation of mitotic spindle organization / cellular response to cAMP / cellular response to forskolin / sensory perception of pain / cellular response to transforming growth factor beta stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / response to nicotine / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / acute-phase response / Post-translational protein phosphorylation / Olfactory Signaling Pathway / G-protein beta/gamma-subunit complex binding / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to peptide hormone / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / response to toxic substance / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / cellular response to virus / Vasopressin regulates renal water homeostasis via Aquaporins / osteoblast differentiation / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / response to calcium ion / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / GDP binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / G alpha (12/13) signalling events / extracellular vesicle / transmembrane signaling receptor activity / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / response to estradiol / retina development in camera-type eye / GTPase binding / Ca2+ pathway / cellular response to oxidative stress / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation
Similarity search - Function
Proenkephalin A / Opioid neuropeptide precursor / Vertebrate endogenous opioids neuropeptide / Endogenous opioids neuropeptides precursors signature. / Mas-related G protein-coupled receptor family / G-protein alpha subunit, group I / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit ...Proenkephalin A / Opioid neuropeptide precursor / Vertebrate endogenous opioids neuropeptide / Endogenous opioids neuropeptides precursors signature. / Mas-related G protein-coupled receptor family / G-protein alpha subunit, group I / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Proenkephalin-A / 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 X1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsSun JP / Xu HE / Yang F / Liu ZM / Guo LL / Zhang YM / Fang GX / Tie L / Zhuang YM / Xue CY
Funding support China, 2 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)91939301 China
National Natural Science Foundation of China (NSFC)32130022 China
CitationJournal: Nat Commun / Year: 2023
Title: Ligand recognition and G protein coupling of the human itch receptor MRGPRX1.
Authors: Lulu Guo / Yumu Zhang / Guoxing Fang / Lu Tie / Yuming Zhuang / Chenyang Xue / Qi Liu / Minghui Zhang / Kongkai Zhu / Chongzhao You / Peiyu Xu / Qingning Yuan / Chao Zhang / Lei Liu / ...Authors: Lulu Guo / Yumu Zhang / Guoxing Fang / Lu Tie / Yuming Zhuang / Chenyang Xue / Qi Liu / Minghui Zhang / Kongkai Zhu / Chongzhao You / Peiyu Xu / Qingning Yuan / Chao Zhang / Lei Liu / Naikang Rong / Shengxuan Peng / Yuan Liu / Chuanzheng Wang / Xin Luo / Zongyao Lv / Dongwei Kang / Xiao Yu / Cheng Zhang / Yi Jiang / Xinzhong Dong / Jiuyao Zhou / Zhongmin Liu / Fan Yang / H Eric Xu / Jin-Peng Sun /
Abstract: MRGPRX1, a Mas-related GPCR (MRGPR), is a key receptor for itch perception and targeting MRGPRX1 may have potential to treat both chronic itch and pain. Here we report cryo-EM structures of the ...MRGPRX1, a Mas-related GPCR (MRGPR), is a key receptor for itch perception and targeting MRGPRX1 may have potential to treat both chronic itch and pain. Here we report cryo-EM structures of the MRGPRX1-Gi1 and MRGPRX1-Gq trimers in complex with two peptide ligands, BAM8-22 and CNF-Tx2. These structures reveal a shallow orthosteric pocket and its conformational plasticity for sensing multiple different peptidic itch allergens. Distinct from MRGPRX2, MRGPRX1 contains a unique pocket feature at the extracellular ends of TM3 and TM4 to accommodate the peptide C-terminal "RF/RY" motif, which could serve as key mechanisms for peptidic allergen recognition. Below the ligand binding pocket, the GXPFGXF/W motif is essential for the inward tilting of the upper end of TM6 to induce receptor activation. Moreover, structural features inside the ligand pocket and on the cytoplasmic side of MRGPRX1 are identified as key elements for both Gi and Gq signaling. Collectively, our studies provide structural insights into understanding itch sensation, MRGPRX1 activation, and downstream G protein signaling.
History
DepositionMay 20, 2023-
Header (metadata) releaseJan 10, 2024-
Map releaseJan 10, 2024-
UpdateJan 10, 2024-
Current statusJan 10, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36233.png

Downloads & links

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Map

FileDownload / File: emd_36233.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.89 Å
Density
Contour LevelBy AUTHOR: 0.217
Minimum - Maximum-1.4942596 - 1.9000905
Average (Standard dev.)0.0012622481 (±0.0471752)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 227.84 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36233_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_36233_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22

EntireName: CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22
Components
  • Complex: CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: BAM8-22
    • Protein or peptide: Single-Chain Fragment Variable 16
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Mas-related G-protein coupled receptor member X1

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Supramolecule #1: CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22

SupramoleculeName: CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 6.633625 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
NTASIAQARK LVEQLKMEAN IDRIKVSKAA ADLMAYCEAH AKEDPLLTPV PASENPFREK

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #2: BAM8-22

MacromoleculeName: BAM8-22 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.603797 KDa
SequenceString:
PEWWMDYQKR Y

UniProtKB: Proenkephalin-A

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Macromolecule #3: Single-Chain Fragment Variable 16

MacromoleculeName: Single-Chain Fragment Variable 16 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 30.363043 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFAVQ LVESGGGLVQ PGGSRKLSCS ASGFAFSSFG MHWVRQAPEK GLEWVAYIS SGSGTIYYAD TVKGRFTISR DDPKNTLFLQ MTSLRSEDTA MYYCVRSIYY YGSSPFDFWG QGTTLTVSAG G GGSGGGGS ...String:
MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFAVQ LVESGGGLVQ PGGSRKLSCS ASGFAFSSFG MHWVRQAPEK GLEWVAYIS SGSGTIYYAD TVKGRFTISR DDPKNTLFLQ MTSLRSEDTA MYYCVRSIYY YGSSPFDFWG QGTTLTVSAG G GGSGGGGS GGGGSADIVM TQATSSVPVT PGESVSISCR SSKSLLHSNG NTYLYWFLQR PGQSPQLLIY RMSNLASGVP DR FSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GAGTKLEL

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Macromolecule #4: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.415031 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCA TDTKNVQFVF DAVTDVIIKN NLKDCGLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.561152 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: LEVLFQGPCG SSGSELDQLR QEAEQLKNQI RDARKACADA TLSQITNNID PVGRIQMRTR RTLRGHLAKI YAMHWGTDSR LLVSASQDG KLIIWDSYTT NKVHAIPLRS SWVMTCAYAP SGNYVACGGL DNICSIYNLK TREGNVRVSR ELAGHTGYLS C CRFLDDNQ ...String:
LEVLFQGPCG SSGSELDQLR QEAEQLKNQI RDARKACADA TLSQITNNID PVGRIQMRTR RTLRGHLAKI YAMHWGTDSR LLVSASQDG KLIIWDSYTT NKVHAIPLRS SWVMTCAYAP SGNYVACGGL DNICSIYNLK TREGNVRVSR ELAGHTGYLS C CRFLDDNQ IVTSSGDTTC ALWDIETGQQ TTTFTGHTGD VMSLSLAPDT RLFVSGACDA SAKLWDVREG MCRQTFTGHE SD INAICFF PNGNAFATGS DDATCRLFDL RADQELMTYS HDNIICGITS VSFSKSGRLL LAGYDDFNCN VWDALKADRA GVL AGHDNR VSCLGVTDDG MAVATGSWDS FLKIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #6: Mas-related G-protein coupled receptor member X1

MacromoleculeName: Mas-related G-protein coupled receptor member X1 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.276906 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDPTISTLDT ELTPINGTEE TLCYKQTLSL TVLTCIVSLV GLTGNAVVLW LLGCRMRRNA FSIYILNLAA ADFLFLSGRL IYSLLSFIS IPHTISKILY PVMMFSYFAG LSFLSAVSTE RCLSVLWPIW YRCHRPTHLS AVVCVLLWAL SLLRSILEWM L CGFLFSGA ...String:
MDPTISTLDT ELTPINGTEE TLCYKQTLSL TVLTCIVSLV GLTGNAVVLW LLGCRMRRNA FSIYILNLAA ADFLFLSGRL IYSLLSFIS IPHTISKILY PVMMFSYFAG LSFLSAVSTE RCLSVLWPIW YRCHRPTHLS AVVCVLLWAL SLLRSILEWM L CGFLFSGA DSAWCQTSDF ITVAWLIFLC VVLCGSSLVL LIRILCGSRK IPLTRLYVTI LLTVLVFLLC GLPFGIQFFL FL WIHVDRE VLFCHVHLVS IFLSALNSSA NPIIYFFVGS FRQRQNRQNL KLVLQRALQD ASEVDEGGGQ LPEEILELSG SRL EQ

UniProtKB: Mas-related G-protein coupled receptor member X1

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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: FLOOD BEAM / Imaging mode: DIFFRACTION / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 924644

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