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- EMDB-65192: Cryo-EM structure of the a-KG-OXGR1-Gq complex -

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Entry
Database: EMDB / ID: EMD-65192
TitleCryo-EM structure of the a-KG-OXGR1-Gq complex
Map data
Sample
  • Complex: Cryo-EM structure of the AKG-OXGR1-Gq complex
    • Protein or peptide: Guanine nucleotide-binding protein G(q) subunit alpha isoforms short
    • 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: 2-oxoglutarate receptor 1
    • Protein or peptide: scFv16
  • Ligand: 2-OXOGLUTARIC ACID
KeywordsOXGR1 / Gq / a-KG / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


Class A/1 (Rhodopsin-like receptors) / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits ...Class A/1 (Rhodopsin-like receptors) / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / sensory perception of taste / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / signaling receptor activity / retina development in camera-type eye / GTPase binding / fibroblast proliferation / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / innate immune response / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit ...G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
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 / 2-oxoglutarate receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsTang XJ / Sun JP / Guo LL / Li J / Deng ZL / Xiao WQ / Zhu Y / Zhu KK
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81773704 China
CitationJournal: Cell / Year: 2026
Title: Metabolite-gated vascular contractility switch: OXGR1 activation mechanism enables agonist therapy for rosacea erythema.
Authors: Wenqin Xiao / Yan Zhu / Xinjie Tang / Kongkai Zhu / Weifeng Zhang / Mengting Chen / Kui Cai / San Xu / Zheng Wu / Mei Wang / Jiayi Liu / Linglong Long / Zixin Tan / Aike Wu / Songqi Zhou / ...Authors: Wenqin Xiao / Yan Zhu / Xinjie Tang / Kongkai Zhu / Weifeng Zhang / Mengting Chen / Kui Cai / San Xu / Zheng Wu / Mei Wang / Jiayi Liu / Linglong Long / Zixin Tan / Aike Wu / Songqi Zhou / Zhixiang Zhao / Yan Tang / Yingxue Huang / Ben Wang / Fangfen Liu / Qian Wang / Fan Yang / Dan Jian / Wei Shi / Hongfu Xie / Xiang Chen / Lulu Guo / Zhili Deng / Jinpeng Sun / Ji Li /
Abstract: Rosacea, an inflammatory skin disorder, poses a dilemma owing to limited effectiveness of treatments for pathological vasodilation-mediated erythema. Here, we identify oxoglutaric acid (α-KG) as a ...Rosacea, an inflammatory skin disorder, poses a dilemma owing to limited effectiveness of treatments for pathological vasodilation-mediated erythema. Here, we identify oxoglutaric acid (α-KG) as a rosacea-associated metabolite elevated in patients and correlated with erythema severity. Exogenous α-KG administration ameliorates rosacea-like manifestations in murine models. Mechanistically, α-KG activates OXGR1, a vascular smooth muscle cell (VSMC)-enriched G protein-coupled receptor (GPCR) to induce Gq signaling and enhance MYL9 phosphorylation, promoting VSMC contraction and limiting vasodilation. Cryo-electron microscopy (cryo-EM) structures of OXGR1-Gq complexes bound to α-KG or itaconate reveal a specific bipartite-acid pocket recognizing its endogenous agonist and an activation mechanism distinct from classical GPCRs. Building on these structures, we developed A-1, a synthetic selective OXGR1 agonist that mitigates erythema and inflammation with efficacy comparable to first-line therapy while offering enhanced safety in rosacea-like models. These findings link a metabolite to vascular dysfunction and nominate OXGR1 agonism for precision treatment of erythema and vascular disorders.
History
DepositionJun 28, 2025-
Header (metadata) releaseMar 18, 2026-
Map releaseMar 18, 2026-
UpdateMar 18, 2026-
Current statusMar 18, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_65192.png

Downloads & links

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Map

FileDownload / File: emd_65192.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.)
1.06 Å/pix.
x 256 pix.
= 271.36 Å		1.06 Å/pix.
x 256 pix.
= 271.36 Å		1.06 Å/pix.
x 256 pix.
= 271.36 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.94
Minimum - Maximum-1.2649735 - 26.173829999999999
Average (Standard dev.)0.009222604 (±0.56026816)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 271.36 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_65192_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

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Half map: #2

Fileemd_65192_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Cryo-EM structure of the AKG-OXGR1-Gq complex

EntireName: Cryo-EM structure of the AKG-OXGR1-Gq complex
Components
  • Complex: Cryo-EM structure of the AKG-OXGR1-Gq complex
    • Protein or peptide: Guanine nucleotide-binding protein G(q) subunit alpha isoforms short
    • 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: 2-oxoglutarate receptor 1
    • Protein or peptide: scFv16
  • Ligand: 2-OXOGLUTARIC ACID

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Supramolecule #1: Cryo-EM structure of the AKG-OXGR1-Gq complex

SupramoleculeName: Cryo-EM structure of the AKG-OXGR1-Gq complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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

MacromoleculeName: Guanine nucleotide-binding protein G(q) subunit alpha isoforms short
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.244766 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: TLSAEDKAAV ERSKMIEKQL QKDKQVYRRT LRLLLLGADN SGKSTIVKQM RIYHVNGYSE EECKQYKAVV YSNTIQSIIA IIRAMGRLK IDFGDSARAD DARQLSVLAG AAEEGFMTAE LAGVIKRLWK DSGVQACFNR SREYQLNDSA AYYLNDLDRI A QPNYIPTQ ...String:
TLSAEDKAAV ERSKMIEKQL QKDKQVYRRT LRLLLLGADN SGKSTIVKQM RIYHVNGYSE EECKQYKAVV YSNTIQSIIA IIRAMGRLK IDFGDSARAD DARQLSVLAG AAEEGFMTAE LAGVIKRLWK DSGVQACFNR SREYQLNDSA AYYLNDLDRI A QPNYIPTQ QDVLRTRVKT SGIFETKFQV DKVNFHMFDV GAQRDERRKW IQCFNDVTAI IFVVDSSDYN RLQEALNDFK SI WNNRWLR TISVILFLNK QDLLAEKVLK SKIEDYFPEF ARYTTPEDAT PEPGEDPRVT RAKYFIRKEF VDISTASGDG RHI CYPHFT CSVDTENARR IFNDCKDIIL QMNLREYNLV

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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: 37.198656 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLIIW DSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF LDDNQIVTSS G DTTCALWD ...String:
ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLIIW DSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF LDDNQIVTSS G DTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TFTGHESDIN AICFFPNGNA FA TGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKADRAGVLA GHDNRVSCLG VTD DGMAVA TGSWDSFLKI WN

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: 5.660541 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP F

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

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Macromolecule #4: 2-oxoglutarate receptor 1

MacromoleculeName: 2-oxoglutarate receptor 1 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 33.758148 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DENIPLKMHY LPVIYGIIFL VGFPGNAVVI STYIFKMRPW KSSTIIMLNL ACTDLLYLTS LPFLIHYYAS GENWIFGDFM CKFIRFSFH FNLYSSILFL TCFSIFRYCV IIHPMSCFSI HKTRCAVVAC AVVWIISLVA VIPMTFLITS TNRTNRSACL D LTSSDELN ...String:
DENIPLKMHY LPVIYGIIFL VGFPGNAVVI STYIFKMRPW KSSTIIMLNL ACTDLLYLTS LPFLIHYYAS GENWIFGDFM CKFIRFSFH FNLYSSILFL TCFSIFRYCV IIHPMSCFSI HKTRCAVVAC AVVWIISLVA VIPMTFLITS TNRTNRSACL D LTSSDELN TIKWYNLILT ATTFCLPLVI VTLCYTTIIH TLTHGLQTDS CLKQKARRLT ILLLLAFYVC FLPFHILRVI RI ESRLLSI SCSIENQIHE AYIVSRPLAA LNTFGNLLLY VVVSDNFQQA VCSTVRCK

UniProtKB: 2-oxoglutarate receptor 1

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Macromolecule #5: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 26.277299 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL

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Macromolecule #6: 2-OXOGLUTARIC ACID

MacromoleculeName: 2-OXOGLUTARIC ACID / type: ligand / ID: 6 / Number of copies: 1 / Formula: AKG
Molecular weightTheoretical: 146.098 Da
Chemical component information

ChemComp-AKG:
2-OXOGLUTARIC ACID

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.875 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: EMReady / Number images used: 462777
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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