G-protein-coupled receptor dynamics: Dimerization and activation models compared with experiment

Bruck Taddese, Lisa M. Simpson, Ian D. Wall, Frank E. Blaney, Nathan J. Kidley, Henry S.X. Clark, Richard E. Smith, Graham J.G. Upton, Paul R. Gouldson, George Psaroudakis, Robert P. Bywater, Christopher A. Reynolds

Research output: Contribution to journalReview articlepeer-review

13 Citations (Scopus)


Our previously derived models of the active state of the β 2-adrenergic receptor are compared with recently published X-ray crystallographic structures of activated GPCRs (G-protein-coupled receptors). Thesemolecular dynamics-based models using experimental data derived from biophysical experiments on activation were used to restrain the receptor to an active state that gave high enrichment for agonists in virtual screening. The β 2-adrenergic receptor active model and X-ray structures are in good agreement over both the transmembrane region and the orthosteric binding site, although in some regions the active model is more similar to the active rhodopsin X-ray structures. The general features of the microswitches were well reproduced, but with minor differences, partly because of the unexpected X-ray results for the rotamer toggle switch. In addition, most of the interacting residues between the receptor and the G-protein were identified. This analysis of the modelling has also given important additional insight into GPCR dimerization: re-analysis of results on photoaffinity analogues of rhodopsin provided additional evidence that TM4 (transmembrane helix 4) resides at the dimer interface and that ligands such as bivalent ligands may pass between the mobile helices. A comparison, and discussion, is also carried out between the use of implicit and explicit solvent for active-state modelling.

Original languageEnglish
Pages (from-to)394-399
Number of pages6
JournalBiochemical Society Transactions
Issue number2
Publication statusPublished - 1 Apr 2012
Externally publishedYes


  • β -adrenergic receptor (β -AR)
  • Activation model
  • G-protein
  • G-protein-coupled receptor dimerization (GPCR dimerization)
  • Homology modelling
  • Rotamer toggle switch

ASJC Scopus subject areas

  • Biochemistry


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