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- EMDB-24899: CryoEM structure of Gi-coupled MRGPRX2 with small molecule agonis... -

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Basic information

Entry
Database: EMDB / ID: EMD-24899
TitleCryoEM structure of Gi-coupled MRGPRX2 with small molecule agonist (R)-Zinc-3573
Map data
SampleMRGPRX2-Gi1 (R)-ZINC-3573
  • Soluble cytochrome b562,Mas-related G-protein coupled receptor member X2 chimera
  • (Guanine nucleotide-binding protein ...) x 3
  • scFv16
  • ligand
Function / homology
Function and homology information


mast cell secretagogue receptor activity / mast cell activation / neuropeptide binding / Adenylate cyclase inhibitory pathway / PLC beta mediated events / positive regulation of protein localization to cell cortex / G protein-coupled serotonin receptor binding / cell cortex region / mast cell degranulation / sleep ...mast cell secretagogue receptor activity / mast cell activation / neuropeptide binding / Adenylate cyclase inhibitory pathway / PLC beta mediated events / positive regulation of protein localization to cell cortex / G protein-coupled serotonin receptor binding / cell cortex region / mast cell degranulation / sleep / Olfactory Signaling Pathway / Thromboxane signalling through TP receptor / regulation of cAMP-mediated signaling / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / positive regulation of cytokinesis / Activation of the phototransduction cascade / cellular response to forskolin / regulation of mitotic spindle organization / ADP signalling through P2Y purinoceptor 12 / Prostacyclin signalling through prostacyclin receptor / G-protein activation / Activation of G protein gated Potassium channels / negative regulation of synaptic transmission / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G protein-coupled acetylcholine receptor signaling pathway / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon signaling in metabolic regulation / cardiac muscle cell apoptotic process / G beta:gamma signalling through CDC42 / sensory perception of taste / alkylglycerophosphoethanolamine phosphodiesterase activity / G alpha (z) signalling events / G-protein beta/gamma-subunit complex / rhodopsin mediated signaling pathway / cellular response to catecholamine stimulus / G beta:gamma signalling through BTK / G-protein gamma-subunit binding / Glucagon-type ligand receptors / positive regulation of potassium ion transmembrane transport / Vasopressin regulates renal water homeostasis via Aquaporins / adenylate cyclase-activating dopamine receptor signaling pathway / GTPase activating protein binding / photoreceptor disc membrane / G-protein beta/gamma-subunit complex binding / photoreceptor outer segment membrane / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / G-protein beta-subunit binding / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G beta:gamma signalling through PI3Kgamma / Regulation of insulin secretion / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / ADP signalling through P2Y purinoceptor 1 / G protein-coupled receptor activity / Wnt signaling pathway, calcium modulating pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / ADORA2B mediated anti-inflammatory cytokines production / extracellular vesicle / response to peptide hormone / G protein-coupled receptor binding / sensory perception of pain / phospholipase C-activating G protein-coupled receptor signaling pathway / GTPase binding / retina development in camera-type eye / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / photoreceptor inner segment / G alpha (s) signalling events / G alpha (i) signalling events / GDP binding / G alpha (q) signalling events / negative regulation of inflammatory response to antigenic stimulus / cell population proliferation / midbody / cell body / Ras protein signal transduction / Extra-nuclear estrogen signaling / lysosomal membrane / cellular response to hypoxia / positive regulation of cytosolic calcium ion concentration / platelet activation / protein folding / periplasmic space / electron transfer activity / cell cycle / GTPase activity / G protein-coupled receptor signaling pathway / iron ion binding / centrosome / cell division / membrane raft / synapse / GTP binding / dendrite / protein-containing complex binding
Similarity search - Function
Mas-related G protein-coupled receptor family / Mas-related G protein-coupled receptor X1/X2 / G-protein alpha subunit, group I / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain superfamily / G-protein gamma-like domain ...Mas-related G protein-coupled receptor family / Mas-related G protein-coupled receptor X1/X2 / G-protein alpha subunit, group I / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain superfamily / G-protein gamma-like domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-alpha domain profile. / G protein alpha subunit, helical insertion / G protein alpha subunit / G-protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein coupled receptors family 1 signature. / GPCR, rhodopsin-like, 7TM / G protein-coupled receptor, rhodopsin-like / 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 circular profile. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
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 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Mas-related G-protein coupled receptor member X2
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.58 Å
AuthorsCao C / Fay JF / Gumpper RH / Roth BL
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK) United States
CitationJournal: Nature / Year: 2021
Title: Structure, function and pharmacology of human itch GPCRs.
Authors: Can Cao / Hye Jin Kang / Isha Singh / He Chen / Chengwei Zhang / Wenlei Ye / Byron W Hayes / Jing Liu / Ryan H Gumpper / Brian J Bender / Samuel T Slocum / Brian E Krumm / Katherine Lansu / ...Authors: Can Cao / Hye Jin Kang / Isha Singh / He Chen / Chengwei Zhang / Wenlei Ye / Byron W Hayes / Jing Liu / Ryan H Gumpper / Brian J Bender / Samuel T Slocum / Brian E Krumm / Katherine Lansu / John D McCorvy / Wesley K Kroeze / Justin G English / Jeffrey F DiBerto / Reid H J Olsen / Xi-Ping Huang / Shicheng Zhang / Yongfeng Liu / Kuglae Kim / Joel Karpiak / Lily Y Jan / Soman N Abraham / Jian Jin / Brian K Shoichet / Jonathan F Fay / Bryan L Roth /
Abstract: The MRGPRX family of receptors (MRGPRX1-4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently. Of these, MRGPRX2 and MRGPRX4 are key physiological and ...The MRGPRX family of receptors (MRGPRX1-4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions. MRGPRX2 couples to both G and G in mast cells. Here we describe agonist-stabilized structures of MRGPRX2 coupled to G and G in ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and G. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.
History
DepositionSep 18, 2021-
Header (metadata) releaseNov 17, 2021-
Map releaseNov 17, 2021-
UpdateDec 1, 2021-
Current statusDec 1, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0786
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.0786
  • Imaged by UCSF Chimera
  • Download
  • Surface view with fitted model
  • Atomic models: PDB-7s8o
  • Surface level: 0.0786
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_24899.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.91 Å/pix.
x 256 pix.
= 232.96 Å
0.91 Å/pix.
x 256 pix.
= 232.96 Å
0.91 Å/pix.
x 256 pix.
= 232.96 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.91 Å
Density
Contour LevelBy AUTHOR: 0.0786 / Movie #1: 0.0786
Minimum - Maximum-0.02713061 - 1.8176616
Average (Standard dev.)0.0015452431 (±0.026504053)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 232.96 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.910.910.91
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z232.960232.960232.960
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ256256256
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0271.8180.002

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Supplemental data

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Segmentation: #1

Fileemd_24899_msk_1.map
Projections & Slices
AxesZYX

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Additional map: sharp map

Fileemd_24899_additional_1.map
Annotationsharp map
Projections & Slices
AxesZYX

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Half map: half map

Fileemd_24899_half_map_1.map
Annotationhalf map
Projections & Slices
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Half map: half map

Fileemd_24899_half_map_2.map
Annotationhalf map
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Sample components

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Entire MRGPRX2-Gi1 (R)-ZINC-3573

EntireName: MRGPRX2-Gi1 (R)-ZINC-3573 / Number of Components: 7

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Component #1: protein, MRGPRX2-Gi1 (R)-ZINC-3573

ProteinName: MRGPRX2-Gi1 (R)-ZINC-3573 / Recombinant expression: No
MassTheoretical: 150 MDa
SourceSpecies: Homo sapiens (human)

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Component #2: protein, Soluble cytochrome b562,Mas-related G-protein coupled re...

ProteinName: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X2 chimera
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 54.054625 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #3: protein, Guanine nucleotide-binding protein G(i) subunit alpha-1

ProteinName: Guanine nucleotide-binding protein G(i) subunit alpha-1
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 40.414047 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #4: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 39.418086 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #5: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 7.861143 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #6: protein, scFv16

ProteinName: scFv16 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 28.668922 kDa
SourceSpecies: Mus musculus (house mouse)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #7: ligand, (3R)-N,N-dimethyl-1-[(8S)-5-phenylpyrazolo[1,5-a]pyrimidi...

LigandName: (3R)-N,N-dimethyl-1-[(8S)-5-phenylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-amine
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.307393 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen State: Particle / Method: cryo EM
Sample solutionpH: 7.5
VitrificationCryogen Name: OTHER

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
ImagingMicroscope: FEI TALOS ARCTICA
Electron gunElectron Source: FIELD EMISSION GUN / Accelerating Voltage: 200 kV / Electron Dose: 45 e/Å2 / Illumination Mode: FLOOD BEAM
LensImaging Mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: OTHER

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Image processing

ProcessingMethod: single particle reconstruction / Number of Projections: 705283
3D reconstructionSoftware: cryoSPARC / Resolution: 2.58 Å / Resolution Method: FSC 0.143 CUT-OFF
FSC plot (resolution estimation)

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Atomic model buiding

Output model

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