Modeling GPCR active state conformations: The β 2-adrenergic receptor

Lisa M. Simpson, Ian D. Wall, Frank E. Blaney, Christopher A. Reynolds

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)


The recent publication of several G protein-coupled receptor (GPCR) structures has increased the information available for homology modeling inactive class A GPCRs. Moreover, the opsin crystal structure shows some active features. We have therefore combined information from these two sources to generate an extensively validated model of the active conformation of the β 2-adrenergic receptor. Experimental information on fully active GPCRs from zinc binding studies, site-directed spin labeling, and other spectroscopic techniques has been used in molecular dynamics simulations. The observed conformational changes reside mainly in transmembrane helix 6 (TM6), with additional small but significant changes in TM5 and TM7. The active model has been validated by manual docking and is in agreement with a large amount of experimental work, including site-directed mutagenesis information. Virtual screening experiments show that the models are selective for β-adrenergic agonists over other GPCR ligands, for (R)- over (S)-β-hydroxy agonists and for β 2-selective agonists over β 1-selective agonists. The virtual screens reproduce interactions similar to those generated by manual docking. The C-terminal peptide from a model of the stimulatory G protein, readily docks into the active model in a similar manner to which the C-terminal peptide from transducin, docks into opsin, as shown in a recent opsin crystal structure. This GPCR-G protein model has been used to explain site-directed mutagenesis data on activation. The agreement with experiment suggests a robust model of an active state of the β 2-adrenergic receptor has been produced. The methodology used here should be transferable to modeling the active state of other GPCRs.

Original languageEnglish
Pages (from-to)1441-1457
Number of pages17
JournalProteins: Structure, Function and Bioinformatics
Issue number5
Early online date4 Jan 2011
Publication statusPublished - 1 May 2011
Externally publishedYes


  • Agonist
  • Docking
  • Muscarinic receptor
  • Principle component analysis
  • Restrained molecular dynamics
  • Rigid core analysis
  • Selectivity
  • Virtual screening

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology


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