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New Model of Cystic Fibrosis Transmembrane Conductance Regulator Proposes Active Channel-like Conformation

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dc.contributor Universitat de Vic. Escola Politècnica Superior
dc.contributor Universitat de Vic. Grup de Recerca en Bioinformàtica i Estadística Mèdica
dc.contributor.author Dalton, James
dc.contributor.author Kalid, Ori
dc.contributor.author Schushan, Maya
dc.contributor.author Ben-Tal, Nir
dc.contributor.author Villà-Freixa, Jordi
dc.date.accessioned 2013-01-18T09:18:51Z
dc.date.available 2013-01-18T09:18:51Z
dc.date.created 2012
dc.date.issued 2012
dc.identifier.citation DALTON, James i altres . "New Model of Cystic Fibrosis Transmembrane Conductance Regulator Proposes Active Channel-like Conformation". A: Journal of Chemical Information and Modeling, 2012, vol. 52, núm. 7, pàg. 1842-1853. ca_ES
dc.identifier.issn 1549-9596
dc.identifier.uri http://hdl.handle.net/10854/1994
dc.description.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. ca_ES
dc.format application/pdf
dc.format.extent 12 p. ca_ES
dc.language.iso eng ca_ES
dc.publisher American Chemical Society ca_ES
dc.rights (c) American Chemical Society, 2012
dc.rights Tots els drets reservats ca_ES
dc.subject.other Fibrosi quística ca_ES
dc.title New Model of Cystic Fibrosis Transmembrane Conductance Regulator Proposes Active Channel-like Conformation ca_ES
dc.type info:eu-repo/semantics/article ca_ES
dc.identifier.doi https://doi.org/dx.doi.org/10.1021/ci2005884
dc.relation.publisherversion http://pubs.acs.org/doi/abs/10.1021/ci2005884
dc.rights.accesRights info:eu-repo/semantics/closedAccess ca_ES
dc.type.version info:eu-repo/publishedVersion ca_ES
dc.indexacio Indexat a SCOPUS
dc.indexacio Indexat a WOS/JCR ca_ES

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