Computer simulations of signal transduction mechanism in alpha 1B-adrenergic and m3-muscarinic receptors.

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Molecular dynamics simulations of the hamster alpha 1B-adrenergic and the rat m3-muscarinic seven-helix bundle receptor models have been carried out. The free, agonist-bound and antagonist-bound forms have been considered. Moreover, three mutant forms of the m3-muscarinic receptor (N507-->A, N507-->D and N507-->S) have also been simulated; among these, the N507-->S mutant shows a constitutive activity. A comparative structural/dynamics analysis has been performed to elucidate (i) the perturbations induced by the functionally different ligands upon binding to their target receptor, (ii) the features of the three single-point mutants with respect to the receptor wild type and (iii) the properties shared by the agonist-bound forms of the alpha 1B-adrenergic receptor and the m3-muscarinic receptor and by the constitutively active mutant N507-->S. The consistency obtained between the structural rearrangement of the transmembrane seven-helix bundle models considered, and the experimental pharmacological efficacies of the ligands and of the mutants, constitute an important validation of the 3-D models obtained and allow the inference of the mechanism of ligand- or mutation-induced receptor activation at the molecular level.