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- PDB-9ehs: Structure of a human adenosine A3 receptor complex bound to the c... -

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Basic information

Entry
Database: PDB / ID: 9ehs
TitleStructure of a human adenosine A3 receptor complex bound to the covalent antagonist LUF7602
Components
  • Adenosine receptor A3,adenosine A3 receptor fused to BRIL
  • BAG2 Anti-BRIL Fab Heavy Chain
  • BAG2 Anti-BRIL Fab Light Chain
  • elbow nanobody
KeywordsSIGNALING PROTEIN / G 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 / presynaptic membrane / G alpha (i) signalling events / inflammatory response / negative regulation of cell population proliferation / dendrite / synapse / signal transduction / plasma membrane
Similarity search - Function
Adenosine A3 receptor / Adenosine receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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)
Similarity search - Domain/homology
: / Adenosine receptor A3
Similarity search - Component
Biological speciessynthetic construct (others)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsZhang, L. / Mobbs, J.I. / Glukhova, A. / Thal, D.M.
Funding support Australia, 3items
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, J.I. / Bennetts, F.M. / Venugopal, H. / Nguyen, A.T. / Christopoulos, A. / van der Es, D. / Heitman, L.H. / May, L.T. / Glukhova, A. / Thal, D.M.
History
DepositionNov 24, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 20, 2025Provider: repository / Type: Initial release
Revision 1.1Sep 3, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: BAG2 Anti-BRIL Fab Heavy Chain
K: elbow nanobody
L: BAG2 Anti-BRIL Fab Light Chain
R: Adenosine receptor A3,adenosine A3 receptor fused to BRIL
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,7465
Polymers116,2284
Non-polymers5181
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Antibody BAG2 Anti-BRIL Fab Heavy Chain


Mass: 24539.314 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: synthetic construct (others)
#2: Antibody elbow nanobody


Mass: 15071.431 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: synthetic construct (others)
#3: Antibody BAG2 Anti-BRIL Fab Light Chain


Mass: 23499.129 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: synthetic construct (others)
#4: Protein Adenosine receptor A3,adenosine A3 receptor fused to BRIL


Mass: 53118.230 Da / Num. of mol.: 1 / Mutation: S97R mutation
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADORA3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P0DMS8
#5: Chemical ChemComp-A1BII / LUF7602


Mass: 517.530 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24FN5O6S / Feature type: SUBJECT OF INVESTIGATION
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: Human A3AR-S97R-BRIL-Bag2-Nb complex / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21rc1_5127 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 328104 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 67.81 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00397367
ELECTRON MICROSCOPYf_angle_d0.769210014
ELECTRON MICROSCOPYf_chiral_restr0.0521146
ELECTRON MICROSCOPYf_plane_restr0.00941244
ELECTRON MICROSCOPYf_dihedral_angle_d12.19372625

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