News Brief: Sodium Channel Structure Solved
Linchpins of pain transmission, voltage-gated sodium (Nav) channels generate action potentials in neurons. They are the sites of action of local anesthetics, and popular targets for new analgesic drug development. Mutations in the channels underlie a range of chronic pain conditions (see recent PRF news story). This week, researchers reported the first high-resolution structure of a voltage-gated sodium channel. The paper, from the labs of William Catterall and Ning Zheng at the University of Washington, Seattle, was published online July 10 in Nature.
The 2.70 Å resolution X-ray crystal structure, of the NavAb protein from the bacterium Arcobacter butzleri, shows a channel in a “pre-open” state, with its voltage sensors activated, but the pore closed. The configuration hints at the mechanism of voltage sensing and voltage-dependent gating, as well as the tricks that make the channel permeable only to sodium.
The bacterial channel, while less complex than its human counterpart, is considered a good model for vertebrate channels. The structure reveals sites where pore blockers, including toxins, local anesthetics, and anti-epileptic and anti-arrhythmic drugs, likely bind. The snapshot also shows some additional pockets that should catch the attention of chemists looking for promising spots in which newly designed drugs might lodge.
Editor’s Note: Get more details on this historic structure in the comment from Paul DeCaen, Harvard Medical School, that appears directly below.
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