The Tetrodotoxin Binding Site Is within the Outer Vestibule of the Sodium Channel

被引:96
作者
Fozzard, Harry A. [1 ]
Lipkind, Gregory M. [1 ]
机构
[1] Univ Chicago Hosp, Dept Med, Chicago, IL 60637 USA
来源
MARINE DRUGS | 2010年 / 8卷 / 02期
关键词
marine toxins; Na channels; molecular modeling; MYELINATED NERVE-FIBERS; FROG SKELETAL-MUSCLE; NA+ CHANNEL; ELECTROPHORUS-ELECTRICUS; FUNCTIONAL EXPRESSION; CHEMICAL-MODIFICATION; GUANIDINIUM TOXINS; SELECTIVITY FILTER; SAXITOXIN BINDING; STRUCTURAL MODEL;
D O I
10.3390/md8020219
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Tetrodotoxin and saxitoxin are small, compact asymmetrical marine toxins that block voltage-gated Na channels with high affinity and specificity. They enter the channel pore's outer vestibule and bind to multiple residues that control permeation. Radiolabeled toxins were key contributors to channel protein purification and subsequent cloning. They also helped identify critical structural elements called P loops. Spacial organization of their mutation-identified interaction sites in molecular models has generated a molecular image of the TTX binding site in the outer vestibule and the critical permeation and selectivity features of this region. One site in the channel's domain 1 P loop determines affinity differences in mammalian isoforms.
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页码:219 / 234
页数:16
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