title: Monod-Wyman-Changeux Analysis of Ligand-Gated Ion Channel Mutants.
abstract: We present a framework for computing the gating properties of ligand-gated ion channel mutants using the Monod-Wyman-Changeux (MWC) model of allostery. We derive simple analytic formulas for key functional properties such as the leakiness, dynamic range, half-maximal effective concentration ([EC50]), and effective Hill coefficient, and explore the full spectrum of phenotypes that are accessible through mutations. Specifically, we consider mutations in the channel pore of nicotinic acetylcholine receptor (nAChR) and the ligand binding domain of a cyclic nucleotide-gated (CNG) ion channel, demonstrating how each mutation can be characterized as only affecting a subset of the biophysical parameters. In addition, we show how the unifying perspective offered by the MWC model allows us, perhaps surprisingly, to collapse the plethora of dose-response data from different classes of ion channels into a universal family of curves.
authors.affiliation: Department of Physics, California Institute of Technology , Pasadena, California 91125, United States.
authors.forename: Tal
authors.identifier: 0000-0003-0777-1193
authors.initials: T
authors.lastname: Einav
authors.affiliation: Department of Applied Physics and Division of Biology and Biological Engineering, California Institute of Technology , Pasadena, California 91125, United States.
authors.forename: Rob
authors.identifier: 0000-0003-3082-2809
authors.initials: R
authors.lastname: Phillips
mesh_terms: D001665:Binding Sites; D006801:Humans; D008954:Models, Biological; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D050505:Mutant Proteins; D011978:Receptors, Nicotinic