期刊
ISCIENCE
卷 24, 期 6, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2021.102542
关键词
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资金
- Cystic Fibrosis Canada
- Canadian Institutes of Health Research
- Genome Canada
- Segal McGill Chair in Molecular Oncology
- Terry Fox Research Institute
- Warren Y. Soper Charitable Trust
- Alvin Segal Family Foundation
- Ministry of Science and Higher Education of the Russian Federation
- Canadian Institutes of Health Research grant
- Hospital for Sick Children
The study re-evaluated the binding of VX-770 to CFTR in biological membranes, suggesting that VX-770 may mediate potentiation through multiple sites in the CFTR protein.
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-evaluatedVX-770 binding to CFTR in biological membranes using photo-activatable 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 loop4 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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