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- EMDB-36233: CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22 -
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Open data
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Basic information
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Title | CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22 | |||||||||
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![]() | itch receptor / Mas-related GPCRs / MRGPRX1 / STRUCTURAL PROTEIN | |||||||||
Function / homology | ![]() synaptic vesicle lumen / response to chloroquine / chromaffin granule lumen / opioid peptide activity / neuronal dense core vesicle lumen / aggressive behavior / general adaptation syndrome, behavioral process / positive regulation of behavioral fear response / synaptic signaling via neuropeptide / symmetric synapse ...synaptic vesicle lumen / response to chloroquine / chromaffin granule lumen / opioid peptide activity / neuronal dense core vesicle lumen / aggressive behavior / general adaptation syndrome, behavioral process / positive regulation of behavioral fear response / synaptic signaling via neuropeptide / symmetric synapse / G protein-coupled opioid receptor signaling pathway / response to epinephrine / cell body fiber / cellular response to vitamin D / sensory perception / neuropeptide hormone activity / transmission of nerve impulse / startle response / locomotory exploration behavior / response to immobilization stress / behavioral fear response / neuropeptide signaling pathway / glial cell proliferation / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / D2 dopamine receptor binding / cellular response to transforming growth factor beta stimulus / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to cAMP / axon terminus / sensory perception of pain / cellular response to forskolin / regulation of mitotic spindle organization / Peptide ligand-binding receptors / acute-phase response / Regulation of insulin secretion / Post-translational protein phosphorylation / response to nicotine / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G protein-coupled receptor activity / cellular response to virus / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / response to peptide hormone / G-protein beta/gamma-subunit complex binding / centriolar satellite / 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 / response to toxic substance / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / response to calcium ion / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / 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 / osteoblast differentiation / 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 / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / 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 / transmembrane signaling receptor activity / 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 / sensory perception of taste / response to estradiol / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / G protein activity / GTPase binding / Ca2+ pathway / retina development in camera-type eye Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.0 Å | |||||||||
![]() | Sun JP / Xu HE / Yang F / Liu ZM / Guo LL / Zhang YM / Fang GX / Tie L / Zhuang YM / Xue CY | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 33 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 21 KB 21 KB | Display Display | ![]() |
Images | ![]() | 89.2 KB | ||
Filedesc metadata | ![]() | 6.6 KB | ||
Others | ![]() ![]() | 59.3 MB 59.3 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8jggMC ![]() 8jgbC ![]() 8jgfC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.89 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_36233_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_36233_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22
Entire | Name: CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22 |
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Components |
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-Supramolecule #1: CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22
Supramolecule | Name: CryoEM structure of Gi-coupled MRGPRX1 with peptide agonist BAM8-22 type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: 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 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 6.633625 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: NTASIAQARK LVEQLKMEAN IDRIKVSKAA ADLMAYCEAH AKEDPLLTPV PASENPFREK UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #2: BAM8-22
Macromolecule | Name: BAM8-22 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 1.603797 KDa |
Sequence | String: PEWWMDYQKR Y UniProtKB: Proenkephalin-A |
-Macromolecule #3: Single-Chain Fragment Variable 16
Macromolecule | Name: Single-Chain Fragment Variable 16 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 30.363043 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 |
-Macromolecule #4: Guanine nucleotide-binding protein G(i) subunit alpha-1
Macromolecule | Name: Guanine nucleotide-binding protein G(i) subunit alpha-1 type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 40.415031 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 |
-Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: 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 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 38.561152 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 |
-Macromolecule #6: Mas-related G-protein coupled receptor member X1
Macromolecule | Name: Mas-related G-protein coupled receptor member X1 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 36.276906 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: OTHER |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 924644 |
Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: ANGULAR RECONSTITUTION |