The Complete Crystal Structure of an Open Activated Sodium Channel

Abstract

Voltage-gated sodium channels (Navs) play essential roles in excitable tissues, with the activation and opening of these channels resulting in the initial phase of the action potential. A new high resolution (2.45 A) crystal structure of the NavMs prokaryotic sodium channel, has provided the first view of a complete sodium channel structure, enabling visualisation of the interactions of the voltage sensor (VS), S4-S5 linker, pore, and C-terminal domains. The structure has a canonical activated conformation for its VS S4 helix, with a novel S4-S5 linker conformation that leads to an open selectivity filter which in turn leads to an open activation gate at the intracellular membrane surface. This ends in a C-terminal domain (CTD) that acts as a “glue” between the monomers that comprise the tetrameric channel. The activated VS conformation produces a heretofore unseen extensively-hydrogen bonded and salt-bridged interaction motif involving a sodium-channel specific S3 Trp, the S4-S5 linker, the end of the S6 transmembrane region and the top of the CTD. The interaction motif involves a number of residues which are conserved across eukaryotic and prokaryotic sodium channels, but not other ion channels. This structure demonstrates for the first time the physical linkage between channel activation and opening, enabling a complete model for the mechanism of sodium channel activation/opening and closing. (∗= these authors contributed equally; supported by grants from the U.K. BBSRC)