Modeling the pore structure of voltage-gated sodium channels in closed, open, and fast-inactivated conformation reveals details of site 1 toxin and local anesthetic binding

Journal of Molecular Modeling
Holger ScheibGraeme M Robertson

Abstract

In this work molecular modeling was applied to generate homology models of the pore region of the Na(v)1.2 and Na(v)1.8 isoforms of human voltage-gated sodium channels. The models represent the channels in the resting, open, and fast-inactivated states. The transmembrane portions of the channels were based on the equivalent domains of the closed and open conformation potassium channels KcsA and MthK, respectively. The critical selectivity loops were modeled using a structural template identified by a novel 3D-search technique and subsequently merged with the transmembrane portions. The resulting draft models were used to study the differences of tetrodotoxin binding to the tetrodotoxin-sensitive Na(v)1.2 (EC50: 0.012 microM) and -insensitive Na(v)1.8 (EC50: 60 microM) isoforms, respectively. Furthermore, we investigated binding of the local anesthetic tetracaine to Na(v)1.8 (EC50: 12.5 microM) in resting, conducting, and fast-inactivated state. In accordance with experimental mutagenesis studies, computational docking of tetrodotoxin and tetracaine provided (1) a description of site 1 toxin and local anesthetic binding sites in voltage-gated sodium channels. (2) A rationale for site 1 toxin-sensitivity versus -insensitivity in ...Continue Reading

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Citations

Jan 6, 2007·Pflügers Archiv : European journal of physiology·Sho-Ya WangGing Kuo Wang
Jan 27, 2010·Pflügers Archiv : European journal of physiology·Angelika LampertAndreas Leffler
Aug 15, 2009·Journal of the American Chemical Society·Brian M Andresen, J Du Bois
Aug 12, 2009·Proceedings of the National Academy of Sciences of the United States of America·Chris R FeldmanMichael E Pfrender
Mar 7, 2012·Proceedings of the National Academy of Sciences of the United States of America·Chris R FeldmanMichael E Pfrender
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May 11, 2016·Proceedings of the National Academy of Sciences of the United States of America·Rhiannon Thomas-Tran, J Du Bois
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