3PDS

Irreversible Agonist-Beta2 Adrenoceptor Complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.50 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.238 
  • R-Value Observed: 0.241 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structure and function of an irreversible agonist-beta(2) adrenoceptor complex

Rosenbaum, D.M.Zhang, C.Lyons, J.A.Holl, R.Aragao, D.Arlow, D.H.Rasmussen, S.G.F.Choi, H.J.Devree, B.T.Sunahara, R.K.Chae, P.S.Gellman, S.H.Dror, R.O.Shaw, D.E.Weis, W.I.Caffrey, M.Gmeiner, P.Kobilka, B.K.

(2011) Nature 469: 236-240

  • DOI: https://doi.org/10.1038/nature09665
  • Primary Citation of Related Structures:  
    3PDS

  • PubMed Abstract: 

    G-protein-coupled receptors (GPCRs) are eukaryotic integral membrane proteins that modulate biological function by initiating cellular signalling in response to chemically diverse agonists. Despite recent progress in the structural biology of GPCRs, the molecular basis for agonist binding and allosteric modulation of these proteins is poorly understood. Structural knowledge of agonist-bound states is essential for deciphering the mechanism of receptor activation, and for structure-guided design and optimization of ligands. However, the crystallization of agonist-bound GPCRs has been hampered by modest affinities and rapid off-rates of available agonists. Using the inactive structure of the human β(2) adrenergic receptor (β(2)AR) as a guide, we designed a β(2)AR agonist that can be covalently tethered to a specific site on the receptor through a disulphide bond. The covalent β(2)AR-agonist complex forms efficiently, and is capable of activating a heterotrimeric G protein. We crystallized a covalent agonist-bound β(2)AR-T4L fusion protein in lipid bilayers through the use of the lipidic mesophase method, and determined its structure at 3.5 Å resolution. A comparison to the inactive structure and an antibody-stabilized active structure (companion paper) shows how binding events at both the extracellular and intracellular surfaces are required to stabilize an active conformation of the receptor. The structures are in agreement with long-timescale (up to 30 μs) molecular dynamics simulations showing that an agonist-bound active conformation spontaneously relaxes to an inactive-like conformation in the absence of a G protein or stabilizing antibody.


  • Organizational Affiliation

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Fusion protein Beta-2 adrenergic receptor/Lysozyme458Homo sapiensTequatrovirus T4Mutation(s): 3 
Gene Names: ADRB2ADRB2RB2AR
EC: 3.2.1.17
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
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ERC
Query on ERC

Download Ideal Coordinates CCD File 
B [auth A]8-hydroxy-5-[(1R)-1-hydroxy-2-({2-[3-methoxy-4-(3-sulfanylpropoxy)phenyl]ethyl}amino)ethyl]quinolin-2(1H)-one
C23 H28 N2 O5 S
WAQRESHSGHIXBV-IBGZPJMESA-N
CLR
Query on CLR

Download Ideal Coordinates CCD File 
C [auth A]CHOLESTEROL
C27 H46 O
HVYWMOMLDIMFJA-DPAQBDIFSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
G [auth A]
H [auth A]
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.50 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.238 
  • R-Value Observed: 0.241 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 282.44α = 90
b = 40.04β = 90
c = 65.21γ = 90
Software Package:
Software NamePurpose
JBluIce-EPICSdata collection
PHASERphasing
BUSTERrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2011-01-12
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-07-26
    Changes: Refinement description, Source and taxonomy
  • Version 1.3: 2023-03-29
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.4: 2023-09-20
    Changes: Data collection, Refinement description