Journal of Medicinal Chemistry · 2009 · 77 citations · 56 references
MedicineBiochemistryPharmacologyCell SignalingMolecular PharmacologyPharmacodynamicsLigand BindingReceptor BindingReceptor ModelingReceptor PharmacologyReceptor PhysiologyReceptor-ligand InteractionsAgonist ActivityAntagonist PotencyG Protein-coupled Receptor Structure-function RelationshipsG-protein-coupled ReceptorsHomologyHomology Modeling Of ReceptorsPartial Agonist EfficacyPartial Agonist Potency
The P2Y(2) receptor, which is activated by UTP, ATP, and dinucleotides, was studied as a prototypical nucleotide-activated GPCR. A combination of receptor mutagenesis, determination of its effects on potency and efficacy of agonists and antagonists, homology modeling, and chemical experiments was applied. R272 (extracellular loop EL3) was found to play a gatekeeper role, presumably responsible for recognition and orientation of the nucleotides. R272 is also directly involved in binding of dinucleotides, which behaved as partial agonists. Y118A (3.37) mutation led to dramatically reduced efficacy of agonists; it is part of the entry channel as well as the triphosphate binding site. While the Y114A (3.33) mutation did not have any effect on agonist activities, the antagonist Reactive Blue 2 (6) was completely inactive at that mutant. The disulfide bridge Cys25-Cys278 was found to be important for agonist potency but neither for agonist efficacy nor for antagonist potency.
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Improved retroviral vectors for gene transfer and expression.
A. Dusty Miller, G J Rosman · PubMed · 1989 · 2K citations
Crystal structure of the human β2 adrenergic G-protein-coupled receptor
Søren G. F. Rasmussen, Hee‐Jung Choi, Daniel M. Rosenbaum et al. · Nature · 2007 · 1.9K citations