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Yorodumi- EMDB-24896: CryoEM structure of Gq-coupled MRGPRX2 with peptide agonist Corti... -
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-Basic information
Entry | Database: EMDB / ID: EMD-24896 | |||||||||
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Title | CryoEM structure of Gq-coupled MRGPRX2 with peptide agonist Cortistatin-14 | |||||||||
Map data | ||||||||||
Sample |
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Function / homology | Function and homology information mast cell secretagogue receptor activity / mast cell activation / sleep / neuropeptide binding / mast cell degranulation / positive regulation of cytokinesis / sensory perception of pain / G protein-coupled receptor activity / Olfactory Signaling Pathway / Activation of the phototransduction cascade ...mast cell secretagogue receptor activity / mast cell activation / sleep / neuropeptide binding / mast cell degranulation / positive regulation of cytokinesis / sensory perception of pain / G protein-coupled receptor activity / 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 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / 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 / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.45 Å | |||||||||
Authors | Cao C / Fay JF / Gumpper RH / Roth BL | |||||||||
Funding support | United States, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_24896.map.gz | 54.9 MB | EMDB map data format | |
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Header (meta data) | emd-24896-v30.xml emd-24896.xml | 22.9 KB 22.9 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_24896_fsc.xml | 6.1 MB | Display | FSC data file |
Images | emd_24896.png | 118.9 KB | ||
Masks | emd_24896_msk_1.map | 64 MB | Mask map | |
Others | emd_24896_additional_1.map.gz emd_24896_half_map_1.map.gz emd_24896_half_map_2.map.gz | 59.5 MB 59.4 MB 59.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-24896 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-24896 | HTTPS FTP |
-Validation report
Summary document | emd_24896_validation.pdf.gz | 614.2 KB | Display | EMDB validaton report |
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Full document | emd_24896_full_validation.pdf.gz | 613.8 KB | Display | |
Data in XML | emd_24896_validation.xml.gz | 403.8 KB | Display | |
Data in CIF | emd_24896_validation.cif.gz | 1.6 MB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-24896 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-24896 | HTTPS FTP |
-Related structure data
Related structure data | 7s8lMC 7s8mC 7s8nC 7s8oC 7s8pC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-10853 (Title: cryoEM structure of Gq-coupled MRGPRX2 with peptide agonist Cortistatin-14 Data size: 3.6 TB Data #1: Unaligned multi-frame micrographs [micrographs - multiframe]) |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_24896.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Voxel size | X=Y=Z: 0.91 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_24896_msk_1.map | ||||||||||||
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Density Histograms |
-Additional map: #1
File | emd_24896_additional_1.map | ||||||||||||
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Density Histograms |
-Half map: #2
File | emd_24896_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: #1
File | emd_24896_half_map_2.map | ||||||||||||
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Density Histograms |
-Sample components
-Entire : MRGPRX2-Gq Cortistatin-14
Entire | Name: MRGPRX2-Gq Cortistatin-14 |
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Components |
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-Supramolecule #1: MRGPRX2-Gq Cortistatin-14
Supramolecule | Name: MRGPRX2-Gq Cortistatin-14 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 150 kDa/nm |
-Macromolecule #1: Mas-related G-protein coupled receptor member X2
Macromolecule | Name: Mas-related G-protein coupled receptor member X2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 37.146957 KDa |
Recombinant expression | Organism: Trichoplusia ni (cabbage looper) |
Sequence | String: GPDPTTPAWG TESTTVNGND QALLLLCGKE TLIPVFLILF IALVGLVGNG FVLWLLGFRM RRNAFSVYVL SLAGADFLFL CFQIINCLV YLSNFFCSIS INFPSFFTTV MTCAYLAGLS MLSTVSTERC LSVLWPIWYR CRRPRHLSAV VCVLLWALSL L LSILEGKF ...String: GPDPTTPAWG TESTTVNGND QALLLLCGKE TLIPVFLILF IALVGLVGNG FVLWLLGFRM RRNAFSVYVL SLAGADFLFL CFQIINCLV YLSNFFCSIS INFPSFFTTV MTCAYLAGLS MLSTVSTERC LSVLWPIWYR CRRPRHLSAV VCVLLWALSL L LSILEGKF CGFLFSDGDS GWCQTFDFIT AAWLIFLFMV LCGSSLALLV RILCGSRGLP LTRLYLTILL TVLVFLLCGL PF GIQWFLI LWIWKDSDVL FCHIHPVSVV LSSLNSSANP IIYFFVGSFR KQWRLQQPIL KLALQRALQD IAEVDHSEGC FRQ GTPEMS RSSLV |
-Macromolecule #2: Cortistatin 14
Macromolecule | Name: Cortistatin 14 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 1.726048 KDa |
Sequence | String: PCKNFFWKTF SSCK |
-Macromolecule #3: Gs-mini-Gq chimera
Macromolecule | Name: Gs-mini-Gq chimera / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 28.084832 KDa |
Recombinant expression | Organism: Trichoplusia ni (cabbage looper) |
Sequence | String: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA ...String: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA RYTTPEDATP EPGEDPRVTR AKYFIRKEFV DISTASGDGR HICYPHFTCA VDTENARRIF NDCKDIILQM NL REYNLV |
-Macromolecule #4: 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: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 37.728152 KDa |
Recombinant expression | Organism: Trichoplusia ni (cabbage looper) |
Sequence | String: GPGSSGSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...String: GPGSSGSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWN |
-Macromolecule #5: 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: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: Trichoplusia ni (cabbage looper) |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L |
-Macromolecule #6: scFv16
Macromolecule | Name: scFv16 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 27.409588 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: 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 KAAALEVLFQ |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 5 mg/mL |
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Buffer | pH: 7.5 |
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 |
Vitrification | Cryogen name: ETHANE-PROPANE |
-Electron microscopy
Microscope | FEI TALOS ARCTICA |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 45.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |