Identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulator
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 inter...
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Elsevier
2021-06-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004221005101 |
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doaj-8c79a33405ed438787e6e0dfeeeb10302021-06-27T04:39:18ZengElsevieriScience2589-00422021-06-01246102542Identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulatorOnofrio Laselva0Zafar Qureshi1Zhi-Wei Zeng2Evgeniy V. Petrotchenko3Mohabir Ramjeesingh4C. Michael Hamilton5Ling-Jun Huan6Christoph H. Borchers7Régis Pomès8Robert Young9Christine E. Bear10Programme in Molecular Medicine, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Medical and Surgical Sciences, University of Foggia, Foggia, ItalyDepartment of Chemistry, Simon Fraser University, Burnaby, CanadaProgramme in Molecular Medicine, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, CanadaSegal Cancer Proteomics Center, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada; Center for Computational and Data-Intensive Science and Engineering, Skolkovo Institute of Science and Technology, Moscow 121205, RussiaProgramme in Molecular Medicine, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, CanadaDepartment of Chemistry, Simon Fraser University, Burnaby, CanadaProgramme in Molecular Medicine, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, CanadaSegal Cancer Proteomics Center, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada; Center for Computational and Data-Intensive Science and Engineering, Skolkovo Institute of Science and Technology, Moscow 121205, Russia; Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, CanadaProgramme in Molecular Medicine, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, CanadaDepartment of Chemistry, Simon Fraser University, Burnaby, CanadaProgramme in Molecular Medicine, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, Canada; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004221005101BiochemistryBiological sciencesBiophysicsMedicineStructural biology |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulator iScience Biochemistry Biological sciences Biophysics Medicine Structural biology |
| author_facet |
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 |
| author_sort |
Onofrio Laselva |
| title |
Identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulator |
| title_short |
Identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulator |
| title_full |
Identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulator |
| title_fullStr |
Identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulator |
| title_full_unstemmed |
Identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulator |
| title_sort |
identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulator |
| publisher |
Elsevier |
| series |
iScience |
| issn |
2589-0042 |
| publishDate |
2021-06-01 |
| description |
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. |
| topic |
Biochemistry Biological sciences Biophysics Medicine Structural biology |
| url |
http://www.sciencedirect.com/science/article/pii/S2589004221005101 |
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