ArticleThe Journal of biological chemistry2012
Conformational changes relevant to channel activity and folding within the first nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 51 citations in OpenAlex.
- Structural investigations connect the disordered N-terminal extension of HypB to the activities of HypB and SlyD in E. coli.Protein science : a publication of the Protein Society · 2025Article
- CFTR Modulators: From Mechanism to Targeted Therapeutics.Handbook of experimental pharmacology · 2024Article
- CFTR Folding: From Structure and Proteostasis to Cystic Fibrosis Personalized Medicine.ACS chemical biology · 2023Review
- Molecular mechanisms of cystic fibrosis - how mutations lead to misfunction and guide therapy.Bioscience reports · 2022Review
- Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR.Cellular and molecular life sciences : CMLS · 2021Article
- Role of Protein Kinase A-Mediated Phosphorylation in CFTR Channel Activity Regulation.Frontiers in physiology · 2021Review
- Full Rescue of F508del-CFTR Processing and Function by CFTR Modulators Can Be Achieved by Removal of Two Regulatory Regions.International journal of molecular sciences · 2020Article
- HK97 gp74 Possesses an α-Helical Insertion in the ββα Fold That Affects Its Metal Binding,Journal of bacteriology · 2020Article
- Rapid therapeutic advances in CFTR modulator science.Pediatric pulmonology · 2018Review
- A novel triple combination of pharmacological chaperones improves F508del-CFTR correction.Scientific reports · 2018Article
- Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression.Scientific reports · 2018Article
- Structural stability of purified human CFTR is systematically improved by mutations in nucleotide binding domain 1.Biochimica et biophysica acta. Biomembranes · 2018Article
- Partial rescue of F508del-cystic fibrosis transmembrane conductance regulator channel gating with modest improvement of protein processing, but not stability, by a dual-acting small molecule.British journal of pharmacology · 2018Article
- Speeding Up the Identification of Cystic Fibrosis Transmembrane Conductance Regulator-Targeted Drugs: An Approach Based on Bioinformatics Strategies and Surface Plasmon Resonance.Molecules (Basel, Switzerland) · 2018Article
- Attenuation of Phosphorylation-dependent Activation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Disease-causing Mutations at the Transmission Interface.The Journal of biological chemistry · 2017Article
- New insights into interactions between the nucleotide-binding domain of CFTR and keratin 8.Protein science : a publication of the Protein Society · 2017Article
- Current insights into the role of PKA phosphorylation in CFTR channel activity and the pharmacological rescue of cystic fibrosis disease-causing mutants.Cellular and molecular life sciences : CMLS · 2017Review
- Molecular modelling and molecular dynamics of CFTR.Cellular and molecular life sciences : CMLS · 2017Review
- Binding screen for cystic fibrosis transmembrane conductance regulator correctors finds new chemical matter and yields insights into cystic fibrosis therapeutic strategy.Protein science : a publication of the Protein Society · 2016Article
- Deletion of Phenylalanine 508 in the First Nucleotide-binding Domain of the Cystic Fibrosis Transmembrane Conductance Regulator Increases Conformational Exchange and Inhibits Dimerization.The Journal of biological chemistry · 2015Article
Corrections and comments
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Authors and funding
13 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Deletion of Phe-508 (F508del) in the first nucleotide binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) leads to defects in folding and channel gating. NMR data on human F508del NBD1 indicate that an H620Q mutant, shown to increase channel open probability, and the dual corrector/potentiator CFFT-001 similarly disrupt interactions between β-strands S3, S9, and S10 and the C-terminal helices H8 and H9, shifting a preexisting conformational equilibrium from helix to coil. CFFT-001 appears to interact with β-strands S3/S9/S10, consistent with docking simulations. Decreases in T(m) from differential scanning calorimetry with H620Q or CFFT-001 suggest direct compound binding to a less thermostable state of NBD1. We hypothesize that, in full-length CFTR, shifting the conformational equilibrium to reduce H8/H9 interactions with the uniquely conserved strands S9/S10 facilitates release of the regulatory region from the NBD dimerization interface to promote dimerization and thereby increase channel open probability. These studies enabled by our NMR assignments for F508del NBD1 provide a window into the conformational fluctuations within CFTR that may regulate function and contribute to folding energetics.
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Registered trials
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