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Identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulator
- Source :
- iScience, Vol 24, Iss 6, Pp 102542- (2021)
- Publication Year :
- 2021
- Publisher :
- Elsevier, 2021.
-
Abstract
- Summary: 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.
- Subjects :
- Biochemistry
Biological sciences
Biophysics
Medicine
Structural biology
Science
Subjects
Details
- Language :
- English
- ISSN :
- 25890042
- Volume :
- 24
- Issue :
- 6
- Database :
- Directory of Open Access Journals
- Journal :
- iScience
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.8c79a33405ed438787e6e0dfeeeb1030
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.isci.2021.102542