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.

Computer simulations of signal transduction mechanism in alpha 1B-adrenergic and m3-muscarinic receptors / Fanelli, Francesca; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe. - In: PROTEIN ENGINEERING. - ISSN 0269-2139. - ELETTRONICO. - 8(1995), pp. 557-564. [10.1093/protein/8.6.557]

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

FANELLI, Francesca;MENZIANI, Maria Cristina;DE BENEDETTI, Pier Giuseppe
1995

Abstract

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.
8
557
564
Computer simulations of signal transduction mechanism in alpha 1B-adrenergic and m3-muscarinic receptors / Fanelli, Francesca; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe. - In: PROTEIN ENGINEERING. - ISSN 0269-2139. - ELETTRONICO. - 8(1995), pp. 557-564. [10.1093/protein/8.6.557]
Fanelli, Francesca; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/305110
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