title: Atomic Structure of the Cystic Fibrosis Transmembrane Conductance Regulator.
abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel evolved from the ATP-binding cassette (ABC) transporter family. In this study, we determined the structure of zebrafish CFTR in the absence of ATP by electron cryo-microscopy to 3.7 Å resolution. Human and zebrafish CFTR share 55% sequence identity, and 42 of the 46 cystic-fibrosis-causing missense mutational sites are identical. In CFTR, we observe a large anion conduction pathway lined by numerous positively charged residues. A single gate near the extracellular surface closes the channel. The regulatory domain, dephosphorylated, is located in the intracellular opening between the two nucleotide-binding domains (NBDs), preventing NBD dimerization and channel opening. The structure also reveals why many cystic-fibrosis-causing mutations would lead to defects either in folding, ion conduction, or gating and suggests new avenues for therapeutic intervention.
authors.affiliation: The Rockefeller University and Howard Hughes Medical Institute, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: The Rockefeller University and Howard Hughes Medical Institute, 1230 York Avenue, New York, NY 10065, USA. Electronic address: juechen@rockefeller.edu.
authors.forename: Jue
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D020285:Cryoelectron Microscopy; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D017510:Protein Folding; D017386:Sequence Homology, Amino Acid; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; C000618329:CFTR protein, zebrafish; D029961:Zebrafish Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: ABC transporter; CFTR; anion channel; atomic structure; cryo-EM