3VG9

Crystal structure of human adenosine A2A receptor with an allosteric inverse-agonist antibody at 2.7 A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody

Hino, T.Arakawa, T.Iwanari, H.Yurugi-Kobayashi, T.Ikeda-Suno, C.Nakada-Nakura, Y.Kusano-Arai, O.Weyand, S.Shimamura, T.Nomura, N.Cameron, A.D.Kobayashi, T.Hamakubo, T.Iwata, S.Murata, T.

(2012) Nature 482: 237-240

  • DOI: https://doi.org/10.1038/nature10750
  • Primary Citation of Related Structures:  
    3VG9, 3VGA

  • PubMed Abstract: 

    G-protein-coupled receptors are the largest class of cell-surface receptors, and these membrane proteins exist in equilibrium between inactive and active states. Conformational changes induced by extracellular ligands binding to G-protein-coupled receptors result in a cellular response through the activation of G proteins. The A(2A) adenosine receptor (A(2A)AR) is responsible for regulating blood flow to the cardiac muscle and is important in the regulation of glutamate and dopamine release in the brain. Here we report the raising of a mouse monoclonal antibody against human A(2A)AR that prevents agonist but not antagonist binding to the extracellular ligand-binding pocket, and describe the structure of A(2A)AR in complex with the antibody Fab fragment (Fab2838). This structure reveals that Fab2838 recognizes the intracellular surface of A(2A)AR and that its complementarity-determining region, CDR-H3, penetrates into the receptor. CDR-H3 is located in a similar position to the G-protein carboxy-terminal fragment in the active opsin structure and to CDR-3 of the nanobody in the active β(2)-adrenergic receptor structure, but locks A(2A)AR in an inactive conformation. These results suggest a new strategy to modulate the activity of G-protein-coupled receptors.


  • Organizational Affiliation

    Iwata Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Adenosine receptor A2a326Homo sapiensMutation(s): 1 
Gene Names: ADORA2AADORA2
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P29274 (Homo sapiens)
Explore P29274 
Go to UniProtKB:  P29274
PHAROS:  P29274
GTEx:  ENSG00000128271 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29274
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
antibody fab fragment light chain214Mus musculusMutation(s): 0 
Entity Groups  
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Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
antibody fab fragment heavy chain226Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LMT
Query on LMT

Download Ideal Coordinates CCD File 
K [auth A]DODECYL-BETA-D-MALTOSIDE
C24 H46 O11
NLEBIOOXCVAHBD-QKMCSOCLSA-N
ZMA
Query on ZMA

Download Ideal Coordinates CCD File 
D [auth A]4-{2-[(7-amino-2-furan-2-yl[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino]ethyl}phenol
C16 H15 N7 O2
PWTBZOIUWZOPFT-UHFFFAOYSA-N
STE
Query on STE

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth A]
I [auth A]
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A]
STEARIC ACID
C18 H36 O2
QIQXTHQIDYTFRH-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
ZMA BindingDB:  3VG9 Ki: min: 0.1, max: 530 (nM) from 26 assay(s)
Kd: min: 0.22, max: 0.33 (nM) from 2 assay(s)
IC50: min: 0.68, max: 81 (nM) from 7 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 121.18α = 90
b = 90.15β = 98.1
c = 113.55γ = 90
Software Package:
Software NamePurpose
MOSFLMdata reduction
PHASERphasing
PHENIXrefinement
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-01
    Type: Initial release
  • Version 1.1: 2012-02-15
    Changes: Database references
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description