Structure of beta2 adrenoceptor bound to carazolol and an intracellular allosteric antagonist

Experimental Data Snapshot

  • Resolution: 2.70 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.226 

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Mechanism of intracellular allosteric beta 2AR antagonist revealed by X-ray crystal structure.

Liu, X.Ahn, S.Kahsai, A.W.Meng, K.C.Latorraca, N.R.Pani, B.Venkatakrishnan, A.J.Masoudi, A.Weis, W.I.Dror, R.O.Chen, X.Lefkowitz, R.J.Kobilka, B.K.

(2017) Nature 548: 480-484

  • DOI: https://doi.org/10.1038/nature23652
  • Primary Citation of Related Structures:  

  • PubMed Abstract: 

    G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects. The majority of GPCR crystal structures published to date were obtained with receptors bound to orthosteric antagonists, and only a few structures bound to allosteric ligands have been reported. Compound 15 (Cmpd-15) is an allosteric modulator of the β 2 adrenergic receptor (β 2 AR) that was recently isolated from a DNA-encoded small-molecule library. Orthosteric β-adrenergic receptor antagonists, known as beta-blockers, are amongst the most prescribed drugs in the world and Cmpd-15 is the first allosteric beta-blocker. Cmpd-15 exhibits negative cooperativity with agonists and positive cooperativity with inverse agonists. Here we present the structure of the β 2 AR bound to a polyethylene glycol-carboxylic acid derivative (Cmpd-15PA) of this modulator. Cmpd-15PA binds to a pocket formed primarily by the cytoplasmic ends of transmembrane segments 1, 2, 6 and 7 as well as intracellular loop 1 and helix 8. A comparison of this structure with inactive- and active-state structures of the β 2 AR reveals the mechanism by which Cmpd-15 modulates agonist binding affinity and signalling.

  • Organizational Affiliation

    Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Tsinghua University, Beijing 100084, China.

Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Chimera protein of Beta-2 adrenergic receptor and Lysozyme500Homo sapiensTequatrovirus T4
This entity is chimeric
Mutation(s): 3 
Gene Names: ADRB2ADRB2RB2AReT4Tp126
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P07550 (Homo sapiens)
Explore P07550 
Go to UniProtKB:  P07550
PHAROS:  P07550
GTEx:  ENSG00000169252 
Find proteins for P00720 (Enterobacteria phage T4)
Explore P00720 
Go to UniProtKB:  P00720
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP00720P07550
Sequence Annotations
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
Query on 8VS

Download Ideal Coordinates CCD File 
F [auth A]4-carbamoyl-N-[(2R)-2-cyclohexyl-2-phenylacetyl]-L-phenylalanyl-3-bromo-N-methyl-L-phenylalaninamide
C34 H39 Br N4 O4
Query on CLR

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D [auth A],
E [auth A]
C27 H46 O
Query on CAU

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G [auth A](2S)-1-(9H-Carbazol-4-yloxy)-3-(isopropylamino)propan-2-ol
C18 H22 N2 O2
Query on EPE

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B [auth A],
C [auth A]
C8 H18 N2 O4 S
Query on BU1

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H [auth A]1,4-BUTANEDIOL
C4 H10 O2
Query on ACM

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C2 H5 N O
Experimental Data & Validation

Experimental Data

  • Resolution: 2.70 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.226 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.46α = 90
b = 75.71β = 90
c = 173.41γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling

Structure Validation

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Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2017-08-16
    Type: Initial release
  • Version 1.1: 2017-08-30
    Changes: Database references
  • Version 1.2: 2017-09-06
    Changes: Database references
  • Version 1.3: 2022-10-12
    Changes: Database references, Other
  • Version 1.4: 2023-10-18
    Changes: Data collection, Refinement description