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The S631A Mutation Causes a Mechanistic Switch in the Block of hERG Channels by CnErg1

Adam P. Hill ^* , T. J. Campbell ^* , P. S. Bansal , P. W. Kuchel  and J. I. Vandenberg ^* 

^* Victor Chang Cardiac Research Institute, New South Wales, Australia; St. Vincent's Hospital Clinical School, University of New South Wales, New South Wales, Australia; and School of Molecular and Microbial Biosciences, University of Sydney, New South Wales, Australia

Correspondence: Address reprint requests and inquiries to J. Vandenberg, Tel.: 61-2-9295-8371; E-mail: j.vandenberg{at}victorchang.edu.au.

We have studied the interaction of CnErg1, a member of the -KTX subfamily of scorpion toxins with the inactivation-deficient S631A hERG channel. In the background of this mutation, we observed a mechanistic switch from turret block, characteristic of the action of -KTXs on Kv11-type channels, to pore plugging, characteristic of -KTX block of Kv1-type channels. We suggest this reflects destabilization of the outer pore (turret region) of hERG allowing access of the toxin molecule to directly plug the conduction pathway.