Identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulator

Onofrio Laselva, Zafar Qureshi, Zhi Wei Zeng, Evgeniy V. Petrotchenko, Mohabir Ramjeesingh, C. Michael Hamilton, Ling Jun Huan, Christoph H. Borchers, Régis Pomès, Robert Young, Christine E. Bear

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


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.

Original languageEnglish
Article number102542
Issue number6
Publication statusPublished - 25 Jun 2021


  • Biochemistry
  • Biological sciences
  • Biophysics
  • Medicine
  • Structural biology


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