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A Model of the Closed Form of the Nicotinic Acetylcholine Receptor M2 Channel Pore

Department of Chemistry and Biochemistry and UCLA-Department of Energy Center for Genomics and Proteomics, University of California, Los Angeles, Los Angeles, California

Correspondence: Address reprint requests to James Bowie, Dept. of Chemistry and Biochemistry and UCLA-Department of Energy Center for Genomics and Proteomics, Boyer Hall, University of California, Los Angeles, 611 Charles E. Young Dr., E. Los Angeles, CA 90095-1570. E-mail: bowie{at}mbi.ucla.edu.

The nicotinic acetylcholine receptor is a neurotransmitter-gated ion channel in the postsynaptic membrane. It is composed of five homologous subunits, each of which contributes one transmembrane helix—the M2 helix—to create the channel pore. The M2 helix from the subunit is capable of forming a channel by itself. Although a model of the receptor was recently proposed based on a low-resolution, cryo-electron microscopy density map, we found that the model does not explain much of the other available experimental data. Here we propose a new model of the M2 channel derived solely from helix packing and symmetry constraints. This model agrees well with experimental results from solid-state NMR, chemical reactivity, and mutagenesis experiments. The model depicts the channel pore, the channel gate, and the residues responsible for cation specificity.

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