title: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR): CLOSED AND OPEN STATE CHANNEL MODELS.
abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette (ABC) transporter superfamily. CFTR controls the flow of anions through the apical membrane of epithelia. Dysfunctional CFTR causes the common lethal genetic disease cystic fibrosis. Transitions between open and closed states of CFTR are regulated by ATP binding and hydrolysis on the cytosolic nucleotide binding domains, which are coupled with the transmembrane (TM) domains forming the pathway for anion permeation. Lack of structural data hampers a global understanding of CFTR and thus the development of "rational" approaches directly targeting defective CFTR. In this work, we explored possible conformational states of the CFTR gating cycle by means of homology modeling. As templates, we used structures of homologous ABC transporters, namely TM(287-288), ABC-B10, McjD, and Sav1866. In the light of published experimental results, structural analysis of the transmembrane cavity suggests that the TM(287-288)-based CFTR model could correspond to a commonly occupied closed state, whereas the McjD-based model could represent an open state. The models capture the important role played by Phe-337 as a filter/gating residue and provide structural information on the conformational transition from closed to open channel.
authors.affiliation: From the Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary, Calgary, Alberta T2N 1N4, Canada and.
authors.forename: Valentina
authors.initials: V
authors.lastname: Corradi
authors.affiliation: Research Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom p.vergani@ucl.ac.uk.
authors.forename: Paola
authors.initials: P
authors.lastname: Vergani
authors.affiliation: From the Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary, Calgary, Alberta T2N 1N4, Canada and tieleman@ucalgary.ca.
authors.forename: D Peter
authors.initials: DP
authors.lastname: Tieleman
mesh_terms: D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D008956:Models, Chemical; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D040681:Structural Homology, Protein
chemical_list: C505032:CFTR protein, human; D011994:Recombinant Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: ABC transporter; chloride transport; cystic fibrosis; cystic fibrosis transmembrane conductance regulator (CFTR); molecular modeling