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- EMDB-34833: Cryo-EM structure of Gq-coupled MRGPRX1 bound with Compound-16 -

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Entry
Database: EMDB / ID: EMD-34833
TitleCryo-EM structure of Gq-coupled MRGPRX1 bound with Compound-16
Map dataCryoEM structure of Gq coupled MRGPRX1 binding with compound 16
Sample
  • Complex: Gq coupled MRGPRX1 bound with compound 16
    • Protein or peptide: Guanine nucleotide-binding protein G(q) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: scFv16
    • Protein or peptide: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X1,LgBit
    • Protein or peptide: Nb35
  • Ligand: N-{2-[(1-aminoisoquinolin-6-yl)oxy]-4-methylphenyl}-2-methoxybenzene-1-sulfonamide
KeywordsGPCR / SIGNALING PROTEIN
Function / homology
Function and homology information


response to chloroquine / G protein-coupled receptor activity / acute-phase response / 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 activation / G protein-coupled acetylcholine receptor signaling pathway ...response to chloroquine / G protein-coupled receptor activity / acute-phase response / 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 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 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / 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 / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / transmembrane signaling receptor activity / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / electron transfer activity / periplasmic space / cell surface receptor signaling pathway / iron ion binding / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / heme binding / protein-containing complex binding / cell surface / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Mas-related G protein-coupled receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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 ...Mas-related G protein-coupled receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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
Similarity search - Domain/homology
Soluble cytochrome b562 / 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 / Mas-related G-protein coupled receptor member X1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse) / Vicugna pacos (alpaca)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsGan B / Yu LY / Ren RB
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: PLoS Biol / Year: 2023
Title: Mechanism of agonist-induced activation of the human itch receptor MRGPRX1.
Authors: Bing Gan / Leiye Yu / Haifeng Yang / Haizhan Jiao / Bin Pang / Yian Chen / Chen Wang / Rui Lv / Hongli Hu / Zhijian Cao / Ruobing Ren /
Abstract: Mas-related G-protein-coupled receptors X1-X4 (MRGPRX1-X4) are 4 primate-specific receptors that are recently reported to be responsible for many biological processes, including itch sensation, pain ...Mas-related G-protein-coupled receptors X1-X4 (MRGPRX1-X4) are 4 primate-specific receptors that are recently reported to be responsible for many biological processes, including itch sensation, pain transmission, and inflammatory reactions. MRGPRX1 is the first identified human MRGPR, and its expression is restricted to primary sensory neurons. Due to its dual roles in itch and pain signaling pathways, MRGPRX1 has been regarded as a promising target for itch remission and pain inhibition. Here, we reported a cryo-electron microscopy (cryo-EM) structure of Gq-coupled MRGPRX1 in complex with a synthetic agonist compound 16 in an active conformation at an overall resolution of 3.0 Å via a NanoBiT tethering strategy. Compound 16 is a new pain-relieving compound with high potency and selectivity to MRGPRX1 over other MRGPRXs and opioid receptor. MRGPRX1 was revealed to share common structural features of the Gq-mediated receptor activation mechanism of MRGPRX family members, but the variable residues in orthosteric pocket of MRGPRX1 exhibit the unique agonist recognition pattern, potentially facilitating to design MRGPRX1-specific modulators. Together with receptor activation and itch behavior evaluation assays, our study provides a structural snapshot to modify therapeutic molecules for itch relieving and analgesia targeting MRGPRX1.
History
DepositionNov 22, 2022-
Header (metadata) releaseMay 31, 2023-
Map releaseMay 31, 2023-
UpdateDec 13, 2023-
Current statusDec 13, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34833.png

Downloads & links

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Map

FileDownload / File: emd_34833.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM structure of Gq coupled MRGPRX1 binding with compound 16
Voxel sizeX=Y=Z: 0.85 Å
Density
Contour LevelBy AUTHOR: 0.174
Minimum - Maximum-1.4584827 - 2.1130204
Average (Standard dev.)-0.0007312755 (±0.048754245)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 244.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half A map

Fileemd_34833_half_map_1.map
Annotationhalf A map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half B map

Fileemd_34833_half_map_2.map
Annotationhalf B map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Gq coupled MRGPRX1 bound with compound 16

EntireName: Gq coupled MRGPRX1 bound with compound 16
Components
  • Complex: Gq coupled MRGPRX1 bound with compound 16
    • Protein or peptide: Guanine nucleotide-binding protein G(q) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: scFv16
    • Protein or peptide: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X1,LgBit
    • Protein or peptide: Nb35
  • Ligand: N-{2-[(1-aminoisoquinolin-6-yl)oxy]-4-methylphenyl}-2-methoxybenzene-1-sulfonamide

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Supramolecule #1: Gq coupled MRGPRX1 bound with compound 16

SupramoleculeName: Gq coupled MRGPRX1 bound with compound 16 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Source (natural)Organism: Homo sapiens (human)

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

MacromoleculeName: Guanine nucleotide-binding protein G(q) subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.855578 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MMGCTLSAED KAAVERSKMI EKQLQKDKQV YRRTLRLLLL GADNSGKSTI VKQMRIYHVN GYSEEECKQY KAVVYSNTIQ SIIAIIRAM GRLKIDFGDS ARADDARQLF VLAGAAEEGF MTAELAGVIK RLWKDSGVQA CFNRSREYQL NDSAAYYLND L DRIAQPNY ...String:
MMGCTLSAED KAAVERSKMI EKQLQKDKQV YRRTLRLLLL GADNSGKSTI VKQMRIYHVN GYSEEECKQY KAVVYSNTIQ SIIAIIRAM GRLKIDFGDS ARADDARQLF VLAGAAEEGF MTAELAGVIK RLWKDSGVQA CFNRSREYQL NDSAAYYLND L DRIAQPNY IPTQQDVLRT RVKTSGIFET KFQVDKVNFH MFDVGAQRDE RRKWIQCFND VTAIIFVVDS SDYNRLQEAL ND FKSIWNN RWLRTISVIL FLNKQDLLAE KVLAGKSKIE DYFPEFARYT TPEDATPEPG EDPRVTRAKY FIRKEFVDIS TAS GDGRHI CYPHFTCSVD TENARRIFND CKDIILQMNL REYNLV

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Macromolecule #2: 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: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.005895 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: HHHHHHHHHH LEVLFQGPGS SGSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSR LLVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE L AGHTGYLS ...String:
HHHHHHHHHH LEVLFQGPGS SGSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSR LLVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE L AGHTGYLS CCRFLDDNQI VTSSGDTTCA LWDIETGQQT TTFTGHTGDV MSLSLAPDTR LFVSGACDAS AKLWDVREGM CR QTFTGHE SDINAICFFP NGNAFATGSD DATCRLFDLR ADQELMTYSH DNIICGITSV SFSKSGRLLL AGYDDFNCNV WDA LKADRA GVLAGHDNRV SCLGVTDDGM AVATGSWDSF LKIWNGASGA SGASGASVSG WRLFKKIS

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

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Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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

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Macromolecule #4: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 27.784896 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAAHHHHHH HH

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Macromolecule #5: Soluble cytochrome b562,Mas-related G-protein coupled receptor me...

MacromoleculeName: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X1,LgBit
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 71.462594 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDKLEVLFQ GPGSADLEDN WETLNDNLKV IEKADNAAQV KDALTKMRAA ALDAQKATPP KLEDKSPDS PEMKDFRHGF DILVGQIDDA LKLANEGKVK EAQAAAEQLK TTRNAYIQKY LMDPTISTLD TELTPINGTE E TLCYKQTL ...String:
MKTIIALSYI FCLVFADYKD DDDKLEVLFQ GPGSADLEDN WETLNDNLKV IEKADNAAQV KDALTKMRAA ALDAQKATPP KLEDKSPDS PEMKDFRHGF DILVGQIDDA LKLANEGKVK EAQAAAEQLK TTRNAYIQKY LMDPTISTLD TELTPINGTE E TLCYKQTL SLTVLTCIVS LVGLTGNAVV LWLLGCRMRR NAFSIYILNL AAADFLFLSG RLIYSLLSFI SIPHTISKIL YP VMMFSYF AGLSFLSAVS TERCLSVLWP IWYRCHRPTH LSAVVCVLLW ALSLLRSILE WMLCGFLFSG ADSAWCQTSD FIT VAWLIF LCVVLCGSSL VLLIRILCGS RKIPLTRLYV TILLTVLVFL LCGLPFGIQF FLFLWIHVDR EVLFCHVHLV SIFL SALNS SANPIIYFFV GSFRQRQNRQ NLKLVLQRAL QDASEVDEGG GQLPEEILEL SGSRLEQGSA GSVFTLEDFV GDWEQ TAAY NLDQVLEQGG VSSLLQNLAV SVTPIQRIVR SGENALKIDI HVIIPYEGLS ADQMAQIEEV FKVVYPVDDH HFKVIL PYG TLVIDGVTPN MLNYFGRPYE GIAVFDGKKI TVTGTLWNGN KIIDERLITP DGSMLFRVTI NSLEHHHHHH HHHH

UniProtKB: Soluble cytochrome b562, Mas-related G-protein coupled receptor member X1

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Macromolecule #6: Nb35

MacromoleculeName: Nb35 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Vicugna pacos (alpaca)
Molecular weightTheoretical: 17.057271 KDa
Recombinant expressionOrganism: Bacteria (eubacteria)
SequenceString:
MKYLLPTAAA GLLLLAAQPA MAMQVQLQES GGGLVQPGGS LRLSCAASGF TFSNYKMNWV RQAPGKGLEW VSDISQSGAS ISYTGSVKG RFTISRDNAK NTLYLQMNSL KPEDTAVYYC ARCPAPFTRD CFDVTSTTYA YRGQGTQVTV SSHHHHHH

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Macromolecule #7: N-{2-[(1-aminoisoquinolin-6-yl)oxy]-4-methylphenyl}-2-methoxybenz...

MacromoleculeName: N-{2-[(1-aminoisoquinolin-6-yl)oxy]-4-methylphenyl}-2-methoxybenzene-1-sulfonamide
type: ligand / ID: 7 / Number of copies: 1 / Formula: U2U
Molecular weightTheoretical: 435.496 Da
Chemical component information

ChemComp-U2U:
N-{2-[(1-aminoisoquinolin-6-yl)oxy]-4-methylphenyl}-2-methoxybenzene-1-sulfonamide

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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: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 56.15 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1006848

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