Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor

摘要: G protein-coupled receptors constitute the largest family of membrane and modulate almost every physiological process in humans. Binding agonists to induces a shift from inactive active receptor conformations. Biophysical studies dynamic equilibrium suggest that portion can remain states even presence saturating concentrations agonist protein mimetic. However, molecular details agonist-bound are poorly understood. Here we use model bitopic orthosteric/allosteric (i.e. dualsteric) for muscarinic M2 demonstrate existence function such agonist·receptor complexes on level. Using all-atom dynamics simulations, dynophores combination static three-dimensional pharmacophores dynamics-based conformational sampling), ligand design, mutagenesis, show result binding allosteric vestibule alone, whereas dualsteric mode produces receptors. Each forms distinct ensemble, different efficacies depend fraction purely inactive) versus active) modes. We propose this concept may explain why be adopting multiple modes generalized also small where will only subtly confined one site.