title: Molecular details of the activation of the μ opioid receptor.
abstract: Molecular details of μ opioid receptor activations were obtained using molecular dynamics simulations of the receptor in the presence of three agonists, three antagonists, and a partial agonist and on the constitutively active T279K mutant. Agonists have a higher probability of direct interactions of their basic nitrogen (N) with Asp147 as compared with antagonists, indicating that direct ligand-Asp147 interactions modulate activation. Medium-size substituents on the basic N of antagonists lead to steric interactions that perturb N-Asp147 interactions, while additional favorable interactions occur with larger basic N substituents, such as in N-phenethylnormorphine, restoring N-Asp147 interactions, leading to agonism. With the orvinols, the increased size of the C19 substituent in buprenorphine over diprenorphine leads to increased interactions with residues adjacent to Asp147, partially overcoming the presence of the cyclopropyl N substituent, such that buprenorphine is a partial agonist. Results also indicate different conformational properties of the intracellular regions of the transmembrane helices in agonists versus antagonists.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, USA.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Shim
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
mesh_terms: D000818:Animals; D008024:Ligands; D051379:Mice; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009022:Morphine Derivatives / Q000737:chemistry / Q000494:pharmacology; D017354:Point Mutation; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D009022:Morphine Derivatives; D017450:Receptors, Opioid, mu; C010616:normorphine