Ivacaftor (VX-770) was the first cystic fibrosis transmembrane conductance regulator (CFTR) modulatory drug approved for the treatment of patients with cystic fibrosis. Electron cryomicroscopy (cryo-EM) studies of detergent-solubilized CFTR indicated that VX-770 bound to a site at the interface between solvent and a hinge region in the CFTR protein conferred by transmembrane (tm) helices: tm4, tm5, and tm8. We re-evaluated VX-770 binding to CFTR in biological membranes using photoactivatable VX-770 probes. One such probe covalently labeled CFTR at two sites as determined following trypsin digestion and analysis by tandem-mass spectrometry. One labeled peptide resides in the cytosolic loop 4 of CFTR and the other is located in tm8, proximal to the site identified by cryo-EM. Complementary data from functional and molecular dynamic simulation studies support a model, where VX-770 mediates potentiation via multiple sites in the CFTR protein.
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http://dx.doi.org/10.1016/j.isci.2021.102542 | DOI Listing |
Sci Rep
December 2024
Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
The lungs of people with cystic fibrosis (PwCF) are characterized by recurrent bacterial infections and inflammation. Infections in cystic fibrosis (CF) are left unresolved despite excessive neutrophil infiltration. The role of CFTR in neutrophils is not fully understood.
View Article and Find Full Text PDFCan J Diabetes
December 2024
Division of Endocrinology & Metabolism, Department of Medicine, Nova Scotia Health. QEII - Victoria Building, Suite 7-North-046 Victoria Building, 1276 South Park Street, Halifax, Nova Scotia, Canada, B3H 2Y9.
J Biol Chem
December 2024
Physiology & Biomedical Engineering, Mayo Clinic College of Medicine & Science, Rochester, MN, 55906; Nephrology & Hypertension, Mayo Clinic College of Medicine & Science, Rochester, MN, 55906. Electronic address:
The chloride transporter-channel SLC26A9 is mediated by a reciprocal regulatory mechanism through the interaction between its cytoplasmic STAS domain and the R domain of CFTR. In vertebrate Slc26a9s, the STAS domain structures are interrupted by a disordered loop which is conserved in mammals but is variable in non-mammals. Despite the numerous studies involving the STAS domains in SLC26 proteins, the role of the disordered loop region has not been identified.
View Article and Find Full Text PDFSci Rep
December 2024
Airway Innate Immunity Research Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK.
Mesenchymal stromal cells (MSCs) are multipotent adult stem cells which possess immunomodulatory and repair capabilities. In this study, we investigated whether MSC therapy could modulate inflammation and lung damage in the lungs of Scnn1b-transgenic mice overexpressing the β-subunit of the epithelial sodium channel (β-ENaC), a model with features of Cystic Fibrosis lung disease. Human bone marrow derived MSC cells were intravenously delivered to mice, prior to collection of bronchoalveolar lavage (BALF) and tissue.
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