Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylationdependent but ATP-independent manner

Abstract

Background: VX-770 (ivacaftor), approved for therapy in CF patients bearing the G551D mutation, has an unknown mode of action. Results: Potentiation of purified WT and mutant CFTR by VX-770 did not require the normal activating ligand ATP. Conclusion: VX-770 binds WT and mutant CFTR channels directly to induce a nonconventional mode of gating. Significance: These findings will enable discovery of the VX-770-binding site. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.