Structural identification of a hotspot on CFTR for potentiation

Science. 2019 Jun 21;364(6446):1184-1188. doi: 10.1126/science.aaw7611.


Cystic fibrosis is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Two main categories of drugs are being developed: correctors that improve folding of CFTR and potentiators that recover the function of CFTR. Here, we report two cryo-electron microscopy structures of human CFTR in complex with potentiators: one with the U.S. Food and Drug Administration (FDA)-approved drug ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These two drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggests that in both cases, hydrogen bonds provided by the protein are important for drug recognition. The molecular details of how ivacaftor and GLPG1837 interact with CFTR may facilitate structure-based optimization of therapeutic compounds.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminophenols / chemistry*
  • Aminophenols / pharmacology
  • Binding Sites
  • Chloride Channel Agonists / chemistry*
  • Chloride Channel Agonists / pharmacology
  • Chloride Channel Agonists / therapeutic use
  • Cryoelectron Microscopy
  • Cystic Fibrosis / drug therapy
  • Cystic Fibrosis Transmembrane Conductance Regulator / chemistry*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Drugs, Investigational / chemistry*
  • Drugs, Investigational / pharmacology
  • Drugs, Investigational / therapeutic use
  • HEK293 Cells
  • Humans
  • Hydrogen Bonding
  • Mutagenesis
  • Protein Domains
  • Protein Folding / drug effects
  • Pyrans / chemistry*
  • Pyrans / pharmacology
  • Pyrans / therapeutic use
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Quinolones / chemistry*
  • Quinolones / pharmacology


  • Aminophenols
  • CFTR protein, human
  • Chloride Channel Agonists
  • Drugs, Investigational
  • GLPG1837
  • Pyrans
  • Pyrazoles
  • Quinolones
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • ivacaftor