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- EMDB-47880: Human adenosine A3 receptor Gi complex (mini-Gsi chimera) bound t... -

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Entry
Database: EMDB / ID: EMD-47880
TitleHuman adenosine A3 receptor Gi complex (mini-Gsi chimera) bound to Piclidenoson (CF101, IB-MECA)
Map dataConsensus map
Sample
  • Complex: Human A3AR-miniGsi1-Gb1g2-Nb35 complex.
    • Protein or peptide: Adenosine receptor A3
    • Protein or peptide: mini-Gs/i chimera
    • 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: Nb35
  • Ligand: Piclidenoson
KeywordsG protein-coupled receptor / adenosine binding / seven transmembrane protein / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of norepinephrine secretion / Adenosine P1 receptors / G protein-coupled adenosine receptor activity / G protein-coupled adenosine receptor signaling pathway / negative regulation of NF-kappaB transcription factor activity / regulation of heart contraction / activation of adenylate cyclase activity / presynaptic modulation of chemical synaptic transmission / negative regulation of cell migration / response to wounding ...regulation of norepinephrine secretion / Adenosine P1 receptors / G protein-coupled adenosine receptor activity / G protein-coupled adenosine receptor signaling pathway / negative regulation of NF-kappaB transcription factor activity / regulation of heart contraction / activation of adenylate cyclase activity / presynaptic modulation of chemical synaptic transmission / negative regulation of cell migration / response to wounding / Schaffer collateral - CA1 synapse / 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 / G beta:gamma signalling through CDC42 / 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / 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 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / presynaptic membrane / GTPase binding / Ca2+ pathway / fibroblast proliferation / 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 / inflammatory response / negative regulation of cell population proliferation / lysosomal membrane / GTPase activity / dendrite / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Adenosine A3 receptor / Adenosine receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 ...Adenosine A3 receptor / Adenosine receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 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. / 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
Adenosine receptor A3 / 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
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsZhang L / Mobbs JI / Glukhova A / Thal DM
Funding support Australia, 3 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)1196951 Australia
National Health and Medical Research Council (NHMRC, Australia)138448 Australia
Australian Research Council (ARC)LP180100560 Australia
Citation
Journal: Nat Commun / Year: 2025
Title: Molecular basis of ligand binding and receptor activation at the human A adenosine receptor.
Authors: Liudi Zhang / Jesse I Mobbs / Felix M Bennetts / Hariprasad Venugopal / Anh T N Nguyen / Arthur Christopoulos / Daan van der Es / Laura H Heitman / Lauren T May / Alisa Glukhova / David M Thal /
Abstract: Adenosine receptors (ARs: AAR, AAR, AAR, and AAR) are crucial therapeutic targets; however, developing selective, efficacious drugs for them remains a significant challenge. Here, we present high- ...Adenosine receptors (ARs: AAR, AAR, AAR, and AAR) are crucial therapeutic targets; however, developing selective, efficacious drugs for them remains a significant challenge. Here, we present high-resolution cryo-electron microscopy (cryo-EM) structures of the human AAR in three distinct functional states: bound to the endogenous agonist adenosine, the clinically relevant agonist Piclidenoson, and the covalent antagonist LUF7602. These structures, complemented by mutagenesis and pharmacological studies, reveal an AAR activation mechanism that involves an extensive hydrogen bond network from the extracellular surface down to the orthosteric binding site. In addition, we identify a cryptic pocket that accommodates the N-iodobenzyl group of Piclidenoson through a ligand-dependent conformational change of M174. Our comprehensive structural and functional characterisation of AAR advances our understanding of adenosine receptor pharmacology and establishes a foundation for developing more selective therapeutics for various disorders, including inflammatory diseases, cancer, and glaucoma.
#1: Journal: Biorxiv / Year: 2025
Title: Molecular basis of ligand binding and receptor activation at the human A3 adenosine receptor
Authors: Zhang L / Mobbs JI / Bennetts FM / Venugopal H / Nguyen AT / Christopoulos A / van der Es D / Heitman LH / May LT / Glukhova A / Thal DM
History
DepositionNov 12, 2024-
Header (metadata) releaseAug 20, 2025-
Map releaseAug 20, 2025-
UpdateSep 3, 2025-
Current statusSep 3, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47880.png

Downloads & links

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Map

FileDownload / File: emd_47880.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationConsensus map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 360 pix.
= 295.2 Å		0.82 Å/pix.
x 360 pix.
= 295.2 Å		0.82 Å/pix.
x 360 pix.
= 295.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.298
Minimum - Maximum-1.1365223 - 2.120504
Average (Standard dev.)0.00043312335 (±0.03995219)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 295.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Local refinement map of A3AR

Fileemd_47880_additional_1.map
AnnotationLocal refinement map of A3AR
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Additional Map

Fileemd_47880_additional_2.map
AnnotationAdditional Map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: Half-map B of consensus map

Fileemd_47880_half_map_1.map
AnnotationHalf-map B of consensus map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map A of consensus map

Fileemd_47880_half_map_2.map
AnnotationHalf-map A of consensus map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : Human A3AR-miniGsi1-Gb1g2-Nb35 complex.

EntireName: Human A3AR-miniGsi1-Gb1g2-Nb35 complex.
Components
  • Complex: Human A3AR-miniGsi1-Gb1g2-Nb35 complex.
    • Protein or peptide: Adenosine receptor A3
    • Protein or peptide: mini-Gs/i chimera
    • 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: Nb35
  • Ligand: Piclidenoson

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Supramolecule #1: Human A3AR-miniGsi1-Gb1g2-Nb35 complex.

SupramoleculeName: Human A3AR-miniGsi1-Gb1g2-Nb35 complex. / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Adenosine receptor A3

MacromoleculeName: Adenosine receptor A3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.203633 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DYKDDDDAAN FTPVNGSSGN QSVRLVTSSS LEVLFQGPPN NSTALSLANV TYITMEIFIG LCAIVGNVLV ICVVKLNPSL QTTTFYFIV SLALADIAVG VLVMPLAIVV SLGITIHFYS CLFMTCLLLI FTHASIMSLL AIAVDRYLRV KLTVRYKRVT T HRRIWLAL ...String:
DYKDDDDAAN FTPVNGSSGN QSVRLVTSSS LEVLFQGPPN NSTALSLANV TYITMEIFIG LCAIVGNVLV ICVVKLNPSL QTTTFYFIV SLALADIAVG VLVMPLAIVV SLGITIHFYS CLFMTCLLLI FTHASIMSLL AIAVDRYLRV KLTVRYKRVT T HRRIWLAL GLCWLVSFLV GLTPMFGWNM KLTSEYHRNV TFLSCQFVSV MRMDYMVYFS FLTWIFIPLV VMCAIYLDIF YI IRNKLSL NLSNSKETGA FYGREFKTAK SLFLVLFLFA LSWLPLSIIN CIIYFNGEVP QLVLYMGILL SHANSMMNPI VYA YKIKKF KETYLLILKA CVVCHPSDSL DTSIEKNSEH HHHHHHH

UniProtKB: Adenosine receptor A3

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Macromolecule #2: mini-Gs/i chimera

MacromoleculeName: mini-Gs/i chimera / type: protein_or_peptide / ID: 2 / Details: Gs-mini-Gi1 chimera / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 29.057938 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GGGSLEVLFQ GPGCTLSAED KAAVERSKMI DRNLREDGEK AAREVKLLLL GADNSGKSTI VKQMRILHGG SGGSGGTSGI FETKFQVDK VNFHMFDVGG QRDERRKWIQ CFNDVTAIIF VVDSSDYNRL QEALNLFKSI WNNRWLRTIS VILFLNKQDL L AEKVLAGK ...String:
GGGSLEVLFQ GPGCTLSAED KAAVERSKMI DRNLREDGEK AAREVKLLLL GADNSGKSTI VKQMRILHGG SGGSGGTSGI FETKFQVDK VNFHMFDVGG QRDERRKWIQ CFNDVTAIIF VVDSSDYNRL QEALNLFKSI WNNRWLRTIS VILFLNKQDL L AEKVLAGK SKIEDYFPEF ARYTTPEDAT PEPGEDPRVT RAKYFIRDEF LRISTASGDG RHYCYPHFTC AVDTENARRI FN DVTDIII KMNLRDCGLF

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Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.402867 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: HHHHHHGSSG SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLI IWDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR F LDDNQIVT ...String:
HHHHHHGSSG SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLI IWDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR F LDDNQIVT SSGDTTCALW DIETGQQTTT FTGHTGDVMS LSLAPDTRLF VSGACDASAK LWDVREGMCR QTFTGHESDI NA ICFFPNG NAFATGSDDA TCRLFDLRAD QELMTYSHDN IICGITSVSF SKSGRLLLAG YDDFNCNVWD ALKADRAGVL AGH DNRVSC LGVTDDGMAV ATGSWDSFLK IWN

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

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Macromolecule #4: 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: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.729947 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
ASNNTASIAQ ARKLVEQLKM EANIDRIKVS KAAADLMAYC EAHAKEDPLL TPVPASENPF REKKFFCAIL

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

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Macromolecule #5: Nb35

MacromoleculeName: Nb35 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 13.885439 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSS

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Macromolecule #6: Piclidenoson

MacromoleculeName: Piclidenoson / type: ligand / ID: 6 / Number of copies: 1 / Formula: Q8L
Molecular weightTheoretical: 510.286 Da
Chemical component information

ChemComp-Q8L:
Piclidenoson

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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

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: Ab initio model
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 589921
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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