G protein‐coupled receptors: a count of 1001 conformations

@article{Vauquelin2005GPR,
  title={G protein‐coupled receptors: a count of 1001 conformations},
  author={Georges Vauquelin and Isabelle Van Liefde},
  journal={Fundamental \& Clinical Pharmacology},
  year={2005},
  volume={19}
}
G protein‐coupled receptors (GPCRs) were initially regarded to adopt an inactive and an active conformation and to activate a single type of G protein. Studies with recombinant cell systems have led to a more complex picture. First, GPCRs can activate distinct G protein species. Second, GPCR multistate models have been invoked to explain their complex behaviour in the presence of agonists, antagonists and other binding partners. The occurrence of intermediate receptor conformational states… 
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References

SHOWING 1-10 OF 95 REFERENCES
G Protein-Coupled Receptor Allosterism and Complexing
TLDR
It is proposed that the study of allosteric phenomena will become of progressively greater import to the drug discovery process due to the advent of newer and more sensitive GPCR screening technologies.
Functionally Different Agonists Induce Distinct Conformations in the G Protein Coupling Domain of the β2Adrenergic Receptor*
TLDR
Monitoring ligand-induced conformational changes in the G protein-coupling domain of the β2 adrenergic receptor provides new insight into the structural consequence of antagonist binding and the basis of agonism and partial agonism.
G-protein-coupled receptor dimerization: modulation of receptor function.
TLDR
This review provides a brief overview of some of the techniques employed to describe GPCR dimers, and discusses their respective limitations, and examines the implications of dimerization/oligomerization on GPCRs function.
G protein-coupled receptor interacting proteins: emerging roles in localization and signal transduction.
TLDR
A review of the recently described GPCR-interacting proteins and their individual functional roles, as understood, suggests that enhancement or disruption of target cell-specific events could serve as highly selective therapeutic opportunities.
Lessons from constitutively active mutants of G protein-coupled receptors
TLDR
Describing how CAMs recapitulate the different structural modifications of the agonist-induced active conformation(s) of the wild-type receptor is a prerequisite for further use of CAMs as ligand-free models of active GPCRs in structural, cellular and physiological studies.
Uncovering molecular mechanisms involved in activation of G protein-coupled receptors.
  • U. Gether
  • Biology, Medicine
    Endocrine reviews
  • 2000
TLDR
The goal of the present review is to specifically address the physical changes linking agonist binding to receptor activation and subsequent transduction of the signal to the associated G protein on the cytoplasmic side of the membrane and to other putative signaling pathways.
Biochemical and pharmacological control of the multiplicity of coupling at G-protein-coupled receptors.
  • E. Hermans
  • Biology, Medicine
    Pharmacology & therapeutics
  • 2003
TLDR
This review aims at summarising the different studies that support the concept of multiplicity of G-protein coupling, and the physiological and pharmacological relevance of this coupling promiscuity will be discussed.
The evolving role of lipid rafts and caveolae in G protein‐coupled receptor signaling: implications for molecular pharmacology
TLDR
The role of lipid rafts and a subpopulation of such rafts, caveolae, is focused on as a key spatial compartment enriched in components of GPCR signal transduction.
Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling.
  • S. Ferguson
  • Biology, Medicine
    Pharmacological reviews
  • 2001
TLDR
The focus of this review is the current and evolving understanding of the contribution of GRKs, beta-arrestins, and endocytosis to GPCR-specific patterns of desensitization and resensitized.
Agonist induction and conformational selection during activation of a G-protein-coupled receptor.
TLDR
It is proposed that agonist induction should be considered as a general mechanism of GPCR activation.
...
1
2
3
4
5
...