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- PDB-8yyw: Cryo-EM structure of OXGR1 bound to alpha-ketoglutarate and Gq pr... -

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Basic information

Entry
Database: PDB / ID: 8yyw
TitleCryo-EM structure of OXGR1 bound to alpha-ketoglutarate and Gq proteins
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • 2-oxoglutarate receptor 1
  • ScFv16
KeywordsMEMBRANE PROTEIN / GPCR / OXGR
Function / homology
Function and homology information


Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / sensory perception of itch / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / regulation of platelet activation / entrainment of circadian clock / Class A/1 (Rhodopsin-like receptors) / regulation of canonical Wnt signaling pathway ...Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / sensory perception of itch / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / regulation of platelet activation / entrainment of circadian clock / Class A/1 (Rhodopsin-like receptors) / regulation of canonical Wnt signaling pathway / glutamate receptor signaling pathway / mast cell degranulation / phototransduction, visible light / photoreceptor outer segment / postsynaptic cytosol / cellular response to acidic pH / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / hormone-mediated signaling pathway / T cell migration / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / cellular response to forskolin / regulation of mitotic spindle organization / GTPase activator activity / chemokine-mediated signaling pathway / Regulation of insulin secretion / neuropeptide signaling pathway / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / response to peptide hormone / G protein-coupled receptor activity / centriolar satellite / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / blood coagulation / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / G beta:gamma signalling through BTK / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / GDP binding / 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 / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / 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 / heterotrimeric G-protein complex / G alpha (12/13) signalling events / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / sensory perception of taste / sperm principal piece / Thrombin signalling through proteinase activated receptors (PARs) / adenylate cyclase-activating G protein-coupled receptor signaling pathway / signaling receptor complex adaptor activity / signaling receptor activity / retina development in camera-type eye / GTPase binding / fibroblast proliferation / G protein activity / midbody / Ca2+ pathway / cell cortex / nuclear membrane / 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 / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction
Similarity search - Function
G-protein alpha subunit, group Q / G-protein alpha subunit, group I / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain ...G-protein alpha subunit, group Q / G-protein alpha subunit, group I / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
2-OXOGLUTARIC ACID / Guanine nucleotide-binding protein G(q) subunit alpha / 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 / 2-oxoglutarate receptor 1
Similarity search - Component
Biological speciesVicugna pacos (alpaca)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.16 Å
AuthorsLiu, A. / Liu, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2025
Title: Molecular insights into ligand recognition and signaling of OXGR1.
Authors: Aijun Liu / Yezhou Liu / Yuanzhengyang Long / Richard D Ye /
Abstract: GPR99/OXGR1 is a G protein-coupled receptor (GPCR) with two endogenous agonists, the tricarboxylic acid cycle derivative 2-oxoglutarate (α-ketoglutarate) and the inflammatory mediator cysteinyl ...GPR99/OXGR1 is a G protein-coupled receptor (GPCR) with two endogenous agonists, the tricarboxylic acid cycle derivative 2-oxoglutarate (α-ketoglutarate) and the inflammatory mediator cysteinyl leukotriene E4 (LTE), hence also termed CysLT3 receptor. How GPR99/OXGR1 recognizes two distinct ligands is a biologically important question. Here we present cryo-EM structures of GPR99/OXGR1-Gq complexed with oxoglutarate and LTE, respectively. The oxoglutarate-bound structure shows a binding pocket surrounded by the transmembrane domains (TM), with a primary site and an accessory site for simultaneous binding of two oxoglutarate molecules for full activation of the receptor. The TM binding pocket, however, is too small to accommodate the cysteinyl leukotriene LTE. Alanine substitution of key residues for oxoglutarate binding had little impact on LTE-induced signaling. A distinct site in between TM3/4/5 just above intracellular loop 2 was identified in the solved structure with LTE, but the densities were less well-defined. Alanine substitution of amino acids potentially involved in LTE interaction at this site abrogated LTE-induced receptor activation without affecting oxoglutarate-induced signaling. Both ligands activated GPR99/OXGR1 primarily through the Gq pathway, but LTE also induced Gi signaling. These findings illustrate the structural basis for GPR99/OXGR1 to interact with structurally distict oxoglutarate and LTE.
History
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: ScFv16
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: 2-oxoglutarate receptor 1
F: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(q) subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)149,0447
Polymers148,7525
Non-polymers2922
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules CDF

#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37285.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 6289.240 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768
#5: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(q) subunit alpha / Adenylate cyclase-inhibiting G alpha protein / Guanine nucleotide-binding protein alpha-q


Mass: 40555.199 Da / Num. of mol.: 1 / Mutation: G203A, A326S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1, GNAQ, GAQ / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096, UniProt: P50148

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Antibody / Protein / Non-polymers , 3 types, 4 molecules BE

#1: Antibody ScFv16


Mass: 26337.307 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Vicugna pacos (alpaca) / Production host: Spodoptera frugiperda (fall armyworm)
#4: Protein 2-oxoglutarate receptor 1 / Alpha-ketoglutarate receptor 1 / G-protein coupled receptor 80 / G-protein coupled receptor 99 / ...Alpha-ketoglutarate receptor 1 / G-protein coupled receptor 80 / G-protein coupled receptor 99 / P2Y purinoceptor 15 / P2Y15 / P2Y-like GPCR / P2Y-like nucleotide receptor


Mass: 38284.020 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: OXGR1, GPR80, GPR99, P2RY15, P2Y15 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96P68
#6: Chemical ChemComp-AKG / 2-OXOGLUTARIC ACID


Mass: 146.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H6O5 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: OXGR1-alpha ketoglutarate-Gq complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.16 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 167941 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0029253
ELECTRON MICROSCOPYf_angle_d0.41112534
ELECTRON MICROSCOPYf_dihedral_angle_d4.0911255
ELECTRON MICROSCOPYf_chiral_restr0.0391435
ELECTRON MICROSCOPYf_plane_restr0.0031582

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