title: Analysis of the selectivity filter of the voltage-gated sodium channel Na(v)Rh.
abstract: NaChBac is a bacterial voltage-gated sodium (Nav) channel that shows sequence similarity to voltage-gated calcium channels. To understand the ion-permeation mechanism of Nav channels, we combined molecular dynamics simulation, structural biology and electrophysiological approaches to investigate the recently determined structure of NavRh, a marine bacterial NaChBac ortholog. Two Na(+) binding sites are identified in the selectivity filter (SF) in our simulations: The extracellular Na(+) ion first approaches site 1 constituted by the side groups of Ser181 and Glu183, and then spontaneously arrives at the energetically more favorable site 2 formed by the carbonyl oxygens of Leu179 and Thr178. In contrast, Ca(2+) ions are prone to being trapped by Glu183 at site 1, which then blocks the entrance of both Na(+) and Ca(2+) to the vestibule of the SF. In addition, Na(+) permeates through the selective filter in an asymmetrical manner, a feature that resembles that of the mammalian Nav orthologs. The study reported here provides insights into the mechanism of ion selectivity on Na(+) over Ca(2+) in mammalian Nav channels.
authors.affiliation: State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Mengdie
authors.initials: M
authors.lastname: Xia
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Huihui
authors.initials: H
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.forename: Wenlin
authors.initials: W
authors.lastname: Ren
authors.forename: Jianping
authors.initials: J
authors.lastname: Wu
authors.forename: Paul
authors.initials: P
authors.lastname: DeCaen
authors.forename: Feng
authors.initials: F
authors.lastname: Yu
authors.forename: Sheng
authors.initials: S
authors.lastname: Huang
authors.forename: Jianhua
authors.initials: J
authors.lastname: He
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
authors.forename: Nieng
authors.initials: N
authors.lastname: Yan
authors.forename: Haipeng
authors.initials: H
authors.lastname: Gong
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D001665:Binding Sites; D004594:Electrophysiology; D056004:Molecular Dynamics Simulation; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D061566:Voltage-Gated Sodium Channels / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; C443666:NaChBac protein, bacteria; D015222:Sodium Channels; D061566:Voltage-Gated Sodium Channels; D012964:Sodium; D011188:Potassium