title: A model of the human M2 muscarinic acetylcholine receptor.
abstract: The M2 muscarinic acetylcholine receptor belongs to the family of rhodopsin like G-Protein Coupled Receptors. This subtype of muscarinic receptors is of special interest because it bears, aside from an orthosteric binding site, also an allosteric binding site. Based on the X-ray structure of bovine rhodopsin a complete homology model of the human M2 receptor was developed. For the orthosteric binding site point mutations and binding studies with different agonists and antagonists are available. This knowledge was utilized for an initial verification of the M2 model. Allosteric modulation of activity is mediated by structurally different ligands such as gallamine, caracurine V salts or W84 (a hexamethonium-derivative). Caracurine V derivatives with different affinities to M2 were docked using GRID-fields. Subsequent molecular dynamics simulations yielded different binding energies based on diverse electrostatic and lipophilic interactions. The calculated affinities are in good agreement to experimentally determined affinities.
authors.affiliation: Institute for Pharmaceutical Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Jöhren
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Höltje
mesh_terms: D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D043585:Receptor, Muscarinic M2 / Q000737:chemistry* / Q000235:genetics; D012243:Rhodopsin / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D043585:Receptor, Muscarinic M2; D012243:Rhodopsin