Crystal structure of NavAP an orthologue of the NaChBac voltage-gated sodium channel

摘要

Voltage-gated sodium (Nav) channels are essential for the rapid depolarization of nerve and muscle, and are important drug targets. A family of bacterial Nav channels, exemplified by NaChBac (Na⁺-selective Channel of Bacteria), provides a good model system for structure-function analysis. Here we report the crystal structure of NavAP, a NaChBac orthologue from marine bacteria alpha proteobacterium HIMB114, at 3.05 Å resolution. The channel comprises an asymmetric tetramer. The carbonyl oxygen atoms of Thr178 and Leu179 constitute an inner site within the selectivity filter (178TLSSWE183) where a Ca²⁺ can bind and resides in the crystal structure. The outer mouth of the Na⁺ selectivity filter, defined by Ser181 and Glu183, is closed, as is the activation gate at the intracellular side of the pore. The voltage sensors adopt a depolarized conformation with all the gating charges exposing to the extracellular side. We hypothesize that NavAP is captured in an inactivated conformation. Comparison of NavAP with NavAb reveals significant conformational rearrangements that may underlie the electromechanical coupling mechanism of voltage-gated channels.