title: An Unaltered Orthosteric Site and a Network of Long-Range Allosteric Interactions for PNU-120596 in α7 Nicotinic Acetylcholine Receptors.
abstract: Nicotinic acetylcholine receptors (nAChRs) are vital to neuronal signaling, are implicated in important processes such as learning and memory, and are therapeutic targets for neural diseases. The α7 nAChR has been implicated in Alzheimer's disease and schizophrenia, and allosteric modulators have become one focus of drug development efforts. We investigate the mode of action of the α7-selective positive allosteric modulator, PNU-120596, and show that the higher potency of acetylcholine in the presence of PNU-120596 is not due to an altered agonist binding site. In addition, we propose several residues in the gating interface and transmembrane region that are functionally important to transduction of allosteric properties, and link PNU-120596, the acetylcholine binding region, and the receptor gate. These results suggest global protein stabilization from a communication network through several key residues that alter the gating equilibrium of the receptor while leaving the agonist binding properties unperturbed.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Marotta
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA. Electronic address: dadougherty@caltech.edu.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Dougherty
mesh_terms: D000109:Acetylcholine / Q000737:chemistry / Q000494:pharmacology; D000494:Allosteric Regulation; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D007555:Isoxazoles; D018722:Nicotinic Agonists; D010671:Phenylurea Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000109:Acetylcholine