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Toxins 2014, 6(12), 3454-3470; doi:10.3390/toxins6123454

Systematic Study of Binding of μ-Conotoxins to the Sodium Channel NaV1.4

School of Physics, University of Sydney, Sydney, New South Wales 2006, Australia
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Received: 7 November 2014 / Revised: 1 December 2014 / Accepted: 10 December 2014 / Published: 18 December 2014
(This article belongs to the Special Issue Ion Channel Neurotoxins)
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Abstract

Voltage-gated sodium channels (NaV) are fundamental components of the nervous system. Their dysfunction is implicated in a number of neurological disorders, such as chronic pain, making them potential targets for the treatment of such disorders. The prominence of the NaV channels in the nervous system has been exploited by venomous animals for preying purposes, which have developed toxins that can block the NaV channels, thereby disabling their function. Because of their potency, such toxins could provide drug leads for the treatment of neurological disorders associated with NaV channels. However, most toxins lack selectivity for a given target NaV channel, and improving their selectivity profile among the NaV1 isoforms is essential for their development as drug leads. Computational methods will be very useful in the solution of such design problems, provided accurate models of the protein-ligand complex can be constructed. Using docking and molecular dynamics simulations, we have recently constructed a model for the NaV1.4-μ-conotoxin-GIIIA complex and validated it with the ample mutational data available for this complex. Here, we use the validated NaV1.4 model in a systematic study of binding other μ-conotoxins (PIIIA, KIIIA and BuIIIB) to NaV1.4. The binding mode obtained for each complex is shown to be consistent with the available mutation data and binding constants. We compare the binding modes of PIIIA, KIIIA and BuIIIB to that of GIIIA and point out the similarities and differences among them. The detailed information about NaV1.4-μ-conotoxin interactions provided here will be useful in the design of new NaV channel blocking peptides. View Full-Text
Keywords: sodium channels; conotoxins; homology modeling; docking; molecular dynamics; potential of mean force; binding free energy sodium channels; conotoxins; homology modeling; docking; molecular dynamics; potential of mean force; binding free energy
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Mahdavi, S.; Kuyucak, S. Systematic Study of Binding of μ-Conotoxins to the Sodium Channel NaV1.4. Toxins 2014, 6, 3454-3470.

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