EMD-0611

Single-particle
3.3 Å
EMD-0611 Deposition: 24/02/2019
Map released: 21/11/2018
Last modified: 15/05/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-0611

Complex of ivacaftor with cystic fibrosis transmembrane conductance regulator (CFTR)

EMD-0611

Single-particle
3.3 Å
EMD-0611 Deposition: 24/02/2019
Map released: 21/11/2018
Last modified: 15/05/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Complex of ivacaftor and cystic fibrosis transmembrane conductance regulator (CFTR)
Fitted models: 6o2p (Avg. Q-score: 0.46)

Deposition Authors: Liu F , Zhang Z
Structural identification of a hotspot on CFTR for potentiation.
Liu F , Zhang Z , Levit A , Levring J , Touhara KK , Shoichet BK , Chen J
(2019) Science , 364 , 1184 - 1188
PUBMED: 31221859
DOI: doi:10.1126/science.aaw7611
ISSN: 1095-9203
ASTM: SCIEAS
Abstract:
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.