Computer simulations of signal transduction mechanism in α1B-adrenergic and m3-muscarinic receptors

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Abstract
Molecular dynamices simulations of the hamster α1Badrenergic 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 recep-tor (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-boundforms of the α1B-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.

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