Modeling active GPCR conformations

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

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

16 Citations (Scopus)


The most significant advance in modeling GPCR active states has been the β2-adrenergic receptor-Gs complex as this essentially transforms active-state modeling into homology modeling. Various different molecular dynamics-based approaches for modeling active states are presented, and a number of key applications discussed. These simulations have given insights into the activation pathway, conformational changes, dimerization, hydration, the ionic lock, ligand binding, protonation, and sodium binding. Crystallography and simulations have shown that the presence of agonist alone is unlikely to be sufficient to form the active state and that restraints applied to the G protein-binding region are required. The role of various microswitches in activation is discussed, including the controversial rotamer toggle switch. The importance of explicitly simulating experimental molecular probes to understand activation is highlighted, along with the need to ensure that such molecules are well parameterized. Approaches to loop modeling are discussed. We argue that the role of successful virtual screening against active models should not be overestimated as the main conformational changes on activation occur in the intracellular region.

Original languageEnglish
Title of host publicationG Protein Coupled ReceptorsModeling, Activation, Interactions and Virtual Screening
PublisherAcademic Press
Number of pages15
ISBN (Print)9780124078659
Publication statusPublished - 29 Jan 2013
Externally publishedYes

Publication series

NameMethods in Enzymology
ISSN (Print)0076-6879
ISSN (Electronic)1557-7988


  • Activation
  • Agonist
  • GPCR
  • Homology modeling
  • Molecular dynamics
  • Restraints
  • Simulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology


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