caa a22 4500 606175377 CHVBK 20210128100742.0 cr unu---uuuuu 210128e20150401xx s 000 0 eng 10.1007/s00018-014-1749-2 doi (NATIONALLICENCE)springer-10.1007/s00018-014-1749-2 Full-open and closed CFTR channels, with lateral tunnels from the cytoplasm and an alternative position of the F508 region, as revealed by molecular dynamics [Elektronische Daten] [Jean-Paul Mornon, Brice Hoffmann, Slavica Jonic, Pierre Lehn, Isabelle Callebaut] In absence of experimental 3D structures, several homology models, based on ABC exporter 3D structures, have provided significant insights into the molecular mechanisms underlying the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel whose defects are associated with cystic fibrosis (CF). Until now, these models, however, did not furnished much insights into the continuous way that ions could follow from the cytosol to the extracellular milieu in the open form of the channel. Here, we have built a refined model of CFTR, based on the outward-facing Sav1866 experimental 3D structure and integrating the evolutionary and structural information available today. Molecular dynamics simulations revealed significant conformational changes, resulting in a full-open channel, accessible from the cytosol through lateral tunnels displayed in the long intracellular loops (ICLs). At the same time, the region of nucleotide-binding domain 1 in contact with one of the ICLs and carrying amino acid F508, the deletion of which is the most common CF-causing mutation, was found to adopt an alternative but stable position. Then, in a second step, this first stable full-open conformation evolved toward another stable state, in which only a limited displacement of the upper part of the transmembrane helices leads to a closure of the channel, in a conformation very close to that adopted by the Atm1 ABC exporter, in an inward-facing conformation. These models, supported by experimental data, provide significant new insights into the CFTR structure-function relationships and into the possible impact of CF-causing mutations. Springer Basel, 2014 CFTR nationallicence ABC exporters nationallicence Chloride channel nationallicence Molecular modeling nationallicence Molecular dynamics nationallicence Mornon Jean-Paul IMPMC, Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 7590, Museum National d'Histoire Naturelle, IRD UMR 206, IUC, Case 115, 4 Place Jussieu, 75005, Paris Cedex 05, France aut Hoffmann Brice IMPMC, Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 7590, Museum National d'Histoire Naturelle, IRD UMR 206, IUC, Case 115, 4 Place Jussieu, 75005, Paris Cedex 05, France aut Jonic Slavica IMPMC, Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 7590, Museum National d'Histoire Naturelle, IRD UMR 206, IUC, Case 115, 4 Place Jussieu, 75005, Paris Cedex 05, France aut Lehn Pierre INSERM U1078, SFR ScInBioS, Université de Bretagne Occidentale, Brest, France aut Callebaut Isabelle IMPMC, Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 7590, Museum National d'Histoire Naturelle, IRD UMR 206, IUC, Case 115, 4 Place Jussieu, 75005, Paris Cedex 05, France aut Cellular and Molecular Life Sciences Springer Basel 72/7(2015-04-01), 1377-1403 1420-682X 72:7<1377 2015 72 18 https://doi.org/10.1007/s00018-014-1749-2 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1749-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Mornon Jean-Paul IMPMC, Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 7590, Museum National d'Histoire Naturelle, IRD UMR 206, IUC, Case 115, 4 Place Jussieu, 75005, Paris Cedex 05, France aut NATIONALLICENCE 700 1- Hoffmann Brice IMPMC, Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 7590, Museum National d'Histoire Naturelle, IRD UMR 206, IUC, Case 115, 4 Place Jussieu, 75005, Paris Cedex 05, France aut NATIONALLICENCE 700 1- Jonic Slavica IMPMC, Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 7590, Museum National d'Histoire Naturelle, IRD UMR 206, IUC, Case 115, 4 Place Jussieu, 75005, Paris Cedex 05, France aut NATIONALLICENCE 700 1- Lehn Pierre INSERM U1078, SFR ScInBioS, Université de Bretagne Occidentale, Brest, France aut NATIONALLICENCE 700 1- Callebaut Isabelle IMPMC, Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 7590, Museum National d'Histoire Naturelle, IRD UMR 206, IUC, Case 115, 4 Place Jussieu, 75005, Paris Cedex 05, France aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/7(2015-04-01), 1377-1403 1420-682X 72:7<1377 2015 72 18