Conservation of chloride channel structure revealed by an inhibitor binding site in ClC-1.

TitleConservation of chloride channel structure revealed by an inhibitor binding site in ClC-1.
Publication TypeJournal Article
Year of Publication2003
AuthorsEstévez R, Schroeder BC, Accardi A, Jentsch TJ, Pusch M
Date Published2003 Apr 10
KeywordsAnimals, Anthracenes, Binding Sites, Chloride Channels, Conserved Sequence, Humans, Ion Channel Gating, Molecular Sequence Data, Mutagenesis, Site-Directed, Oocytes, Patch-Clamp Techniques, Protein Structure, Tertiary, Rats, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Serine, Xenopus

Crystal structures of bacterial CLC proteins were solved recently, but it is unclear to which level of detail they can be extrapolated to mammalian chloride channels. Exploiting the difference in inhibition by 9-anthracene carboxylic acid (9-AC) between ClC-0, -1, and -2, we identified a serine between helices O and P as crucial for 9-AC binding. Mutagenesis based on the crystal structure identified further residues affecting inhibitor binding. They surround a partially hydrophobic pocket close to the chloride binding site that is accessible from the cytoplasm, consistent with the observed intracellular block by 9-AC. Mutations in presumably Cl--coordinating residues yield additional insights into the structure and function of ClC-1. Our work shows that the structure of bacterial CLCs can be extrapolated with fidelity to mammalian Cl- channels.

Alternate JournalNeuron
PubMed ID12691663
Grant List1079 / / Telethon / Italy