@article {Liu1184, author = {Liu, Fangyu and Zhang, Zhe and Levit, Anat and Levring, Jesper and Touhara, Kouki K. and Shoichet, Brian K. and Chen, Jue}, title = {Structural identification of a hotspot on CFTR for potentiation}, volume = {364}, number = {6446}, pages = {1184--1188}, year = {2019}, doi = {10.1126/science.aaw7611}, publisher = {American Association for the Advancement of Science}, abstract = {Cystic fibrosis is a progressive disease that affects lung function and is often fatal. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). One class of mutants impairs ion conductance, and the drug ivacaftor acts by increasing the ion flux. Liu et al. describe high-resolution structures of CFTR bound to ivacaftor and to an investigational drug GLPG1837 that also potentiates ion flow. The two drugs bind at the same site in the transmembrane region. This site coincides with a hinge involved in channel gating, suggesting that the drugs may stabilize the open conformation of the channel.Science, this issue p. 1184Cystic 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{\textendash}electron microscopy structures of human CFTR in complex with potentiators: one with the U.S. Food and Drug Administration (FDA){\textendash}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.}, issn = {0036-8075}, URL = {https://science.sciencemag.org/content/364/6446/1184}, eprint = {https://science.sciencemag.org/content/364/6446/1184.full.pdf}, journal = {Science} }