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Toxins 2012, 4(12), 1552-1564; doi:10.3390/toxins4121552
Article

Binding of Hanatoxin to the Voltage Sensor of Kv2.1

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Received: 26 November 2012; in revised form: 10 December 2012 / Accepted: 14 December 2012 / Published: 18 December 2012
(This article belongs to the Special Issue Animal Venoms)
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Abstract: Hanatoxin 1 (HaTx1) is a polypeptide toxin isolated from spider venoms. HaTx1 inhibits the voltage-gated potassium channel kv2.1 potently with nanomolar affinities. Its receptor site has been shown to contain the S3b-S4a paddle of the voltage sensor (VS). Here, the binding of HaTx1 to the VSs of human Kv2.1 in the open and resting states are examined using a molecular docking method and molecular dynamics. Molecular docking calculations predict two distinct binding modes for the VS in the resting state. In the two binding modes, the toxin binds the S3b-S4a from S2 and S3 helices, or from S1 and S4 helices. Both modes are found to be stable when embedded in a lipid bilayer. Only the mode in which the toxin binds the S3b-S4a paddle from S2 and S3 helices is consistent with mutagenesis experiments, and considered to be correct. The toxin is then docked to the VS in the open state, and the toxin-VS interactions are found to be less favorable. Computational mutagenesis calculations performed on F278R and E281K mutant VSs show that the mutations may reduce toxin binding affinity by weakening the non-bonded interactions between the toxin and the VS. Overall, our calculations reproduce a wide range of experimental data, and suggest that HaTx1 binds to the S3b-S4a paddle of Kv2.1 from S2 and S3 helices.
Keywords: hanatoxin; Kv2.1; voltage sensor; gating modifier toxin; molecular dynamics hanatoxin; Kv2.1; voltage sensor; gating modifier toxin; molecular dynamics
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.

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MDPI and ACS Style

Chen, R.; Robinson, A.; Chung, S.-H. Binding of Hanatoxin to the Voltage Sensor of Kv2.1. Toxins 2012, 4, 1552-1564.

AMA Style

Chen R, Robinson A, Chung S-H. Binding of Hanatoxin to the Voltage Sensor of Kv2.1. Toxins. 2012; 4(12):1552-1564.

Chicago/Turabian Style

Chen, Rong; Robinson, Anna; Chung, Shin-Ho. 2012. "Binding of Hanatoxin to the Voltage Sensor of Kv2.1." Toxins 4, no. 12: 1552-1564.


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