ArticleCellular and molecular life sciences : CMLS2015
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.
Article in Cellular and molecular life sciences : CMLS, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 83 citations in OpenAlex.
- Identification and pharmacological characterization of a natural folipastatin as a CFTR inhibitor and potential anti-secretory agent in a human colonoid model.BMC complementary medicine and therapies · 2025Article
- ABCB4 disease-causing variants S242R, S346I, T437I and T1077M significantly impair its function and display differential sensitivity to potentiators.Scientific reports · 2025Article
- ATP-Binding Cassette and Solute Carrier Transporters: Understanding Their Mechanisms and Drug Modulation Through Structural and Modeling Approaches.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Novel gain-of-function mutants identify a critical region within CFTR membrane-spanning domain 2 controlling cAMP-dependent and ATP-independent channel activation.Cellular and molecular life sciences : CMLS · 2024Article
- Cystic Fibrosis: A Journey through Time and Hope.International journal of molecular sciences · 2024Review
- Molecular mechanisms of cystic fibrosis - how mutations lead to misfunction and guide therapy.Bioscience reports · 2022Review
- The molecular evolution of function in the CFTR chloride channel.The Journal of general physiology · 2021Article
- Stability Prediction for Mutations in the Cytosolic Domains of Cystic Fibrosis Transmembrane Conductance Regulator.Journal of chemical information and modeling · 2021Article
- New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation.Scientific reports · 2021Article
- Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas.FEBS letters · 2020Review
- Recent Strategic Advances in CFTR Drug Discovery: An Overview.International journal of molecular sciences · 2020Review
- Discovering the chloride pathway in the CFTR channel.Cellular and molecular life sciences : CMLS · 2020Article
- Functional and Pharmacological Characterization of the Rare CFTR Mutation W361R.Frontiers in pharmacology · 2020Article
- Unsolved severe chronic rhinosinusitis elucidated by extensiveClinical case reports · 2019Article
- Folding-function relationship of the most common cystic fibrosis-causing CFTR conductance mutants.Life science alliance · 2019Article
- Combining theoretical and experimental data to decipher CFTR 3D structures and functions.Cellular and molecular life sciences : CMLS · 2018Article
- Functional organization of cytoplasmic portals controlling access to the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel pore.The Journal of biological chemistry · 2018Article
- Structural mechanisms of CFTR function and dysfunction.The Journal of general physiology · 2018Review
- Cystic fibrosis transmembrane conductance regulator (CFTR): Making an ion channel out of an active transporter structure.Channels (Austin, Tex.) · 2018Review
- A minimal helical-hairpin motif provides molecular-level insights into misfolding and pharmacological rescue of CFTR.Communications biology · 2018Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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