Российская академия наук



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Tikhonov D.B.1, Zhorov B.S1,2

1Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, 194223; denistikhonov2002@yahoo.com

2Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
Voltage-gated ion channels play critical roles in regulation of neuronal excitability, and their dysfunctions are closely associated with various health disorders. The channels are targets for numerous toxins and medically important drugs. The lack of X-ray structures of mammalian sodium channels prevents structure-based design of new potent and selective pharmacological agents. Recently published X-ray structures of the bacterial sodium channel NavAb provide new templates for studies of sodium and calcium channels. Because the sequence similarity between eukaryotic and prokaryotic sodium channels is poor, the structural similarity is unclear. We analyzed it by using experimental data on channel blocking drugs such as tetrodotoxin and local anesthetics. In a NavAb-based model of Nav1 channels derived from the sequence alignment without insertions/deletions, key tetrodotoxin-sensing residues, so called outer carboxylates, do not face the pore. We proposed that the evolutionary appearance of Nav1 channels involved point deletions between the selectivity filter and the outer carboxylates. The hypothesis allowed building of a NavAb-based model with tetrodotoxin-channel contacts in agreement with experimental data. This hypothesis also allowed us to reproduce in the Nav1 model the folding-stabilizing contacts, which are seen in NavAb. The NavAb-based model of Nav1 reproduced well the data on closed-channel block by local anesthetics, including the access pathway for ligands through the III/IV repeat interface and their interactions with specific ligand-sensing 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, suggesting NavAb as promising basis for homology modeling of calcium channels. We conclude that the X-ray structure of bacterial sodium channel NavAb is suitable structural template for elaboration of new ligands for eukaryotic sodium and calcium channels.

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