title: New model of cystic fibrosis transmembrane conductance regulator proposes active channel-like conformation.
abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is an unusual ABC transporter, functioning as a chloride channel critical for fluid homeostasis in multiple organs. Disruption of CFTR function is associated with cystic fibrosis making it an attractive therapeutic target. In addition, CFTR blockers are being developed as potential antidiarrheals. CFTR drug discovery is hampered by the lack of high resolution structural data, and considerable efforts have been invested in modeling the channel structure. Although previously published CFTR models that have been made publicly available mostly agree with experimental data relating to the overall structure, they present the channel in an outward-facing conformation that does not agree with expected properties of a "channel-like" structure. Here, we make available a model of CFTR in such a "channel-like" conformation, derived by a unique modeling approach combining restrained homology modeling and ROSETTA refinement. In contrast to others, the present model is in agreement with expected channel properties such as pore shape, dimensions, solvent accessibility, and experimentally derived distances. We have used the model to explore the interaction of open channel blockers within the pore, revealing a common binding mode and ionic interaction with K95, in agreement with experimental data. The binding-site was further validated using a virtual screening enrichment experiment, suggesting the model might be suitable for drug discovery. In addition, we subjected the model to a molecular dynamics simulation, revealing previously unaddressed salt-bridge interactions that may be important for structure stability and pore-lining residues that may take part in Cl(-) conductance.
authors: Computational Biochemistry and Biophysics Laboratory, Research Unit on Biomedical Informatics, IMIM Hospital del Mar and Universitat Pompeu Fabra, C/Doctor Aiguader, 88, 08003 Barcelona, Catalunya, Spain.
authors: James
authors: J
authors: Dalton
authors: Ori
authors: O
authors: Kalid
authors: Maya
authors: M
authors: Schushan
authors: Nir
authors: N
authors: Ben-Tal
authors: Jordi
authors: J
authors: Villà-Freixa
mesh_terms: D001665:Binding Sites; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008954:Models, Biological; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D016062:Porosity; D014584:User-Computer Interface
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator