当前位置： SCI文献检索 > MOLECULAR PHARMACOLOGY期刊下所有文献 > Architecture and pore block of eukaryotic voltage-gated sodium channels in view of NavAb bacterial sodium channel structure.

Architecture and pore block of eukaryotic voltage-gated sodium channels in view of NavAb bacterial sodium channel structure.

Abstract：

:The X-ray structure of the bacterial sodium channel NavAb provides a new template for the study of sodium and calcium channels. Unlike potassium channels, NavAb contains P2 helices in the outer-pore region. Because the sequence similarity between eukaryotic and prokaryotic sodium channels in this region is poor, the structural similarity is unclear. We analyzed it by using experimental data on tetrodotoxin block of sodium channels. Key tetrodotoxin-binding residues are outer carboxylates in repeats I, II, and IV, three positions downstream from the selectivity-filter residues. In a NavAb-based model of Nav1 channels derived from the sequence alignment without insertions/deletions, the outer carboxylates did not face the pore and therefore did not interact with tetrodotoxin. The hypothesis that the evolutionary appearance of Nav1 channels involved point deletions in an ancestral channel between the selectivity filter and the outer carboxylates allowed building of a NavAb-based model with tetrodotoxin-channel contacts similar to those proposed previously. This hypothesis also allowed us to reproduce in Nav1 the folding-stabilizing contacts between long-side chain residues in P1 and P2, which are seen in NavAb. The NavAb-based inner-pore model of Nav1 preserved major features of our previous KcsA-based models, including the access pathway for ligands through the repeat III/IV interface and their interactions with specific residues. Thus, structural properties of eukaryotic voltage-gated sodium channels that are suggested by functional data were reproduced in the NavAb-based models built by using the unaltered template structure but with adjusted sequence alignment. Sequences of eukaryotic calcium channels aligned with NavAb without insertions/deletions, which suggests that NavAb is a promising basis for the modeling of calcium channels.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Tikhonov DB,Zhorov BS

doi

10.1124/mol.112.078212

subject

Has Abstract

pub_date

2012-07-01 00:00:00

pages

97-104

issue

eissn

0026-895X

issn

1521-0111

pii

mol.112.078212

journal_volume

pub_type

杂志文章

在线工具

Architecture and pore block of eukaryotic voltage-gated sodium channels in view of NavAb bacterial sodium channel structure.