Computer simulations of signal transduction mechanism in alpha 1B-adrenergic and m3-muscarinic receptors.
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.
Dipartimento di Chimica, Università di Modena, Italy.
F
F
Fanelli
M C
MC
Menziani
P G
PG
De Benedetti
D000316:Adrenergic alpha-Agonists / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism; D000818:Animals; D018678:Cholinergic Agents / Q000378:metabolism; D003198:Computer Simulation; D006224:Cricetinae; D016297:Mutagenesis, Site-Directed; D051381:Rats; D043587:Receptor, Muscarinic M3; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
C547718:Adra1b protein, rat; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018678:Cholinergic Agents; D043587:Receptor, Muscarinic M3; D018340:Receptors, Adrenergic, alpha-1; D011976:Receptors, Muscarinic