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Journal/Book/Conference Title

The Biophysical Journal





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Originally published at

Under an Elsevier user license

Date of Submission

February 2015



Previous studies have shown that the unusually long S5-P linker lining human ether a-go-go related gene’s (hERG’s) outer vestibule is critical for its channel function: point mutations at high-impact positions here can interfere with the inactivation process and, in many cases, also reduce the pore’s K+ selectivity. Because no data are available on the equivalent region in the available K channel crystal structures to allow for homology modeling, we used alternative approaches to model its three-dimensional structure. The first part of this article describes mutant cycle analysis used to identify residues on hERG’s outer vestibule that interact with specific residues on the interaction surface of BeKm-1, a peptide toxin with known NMR structure and a high binding affinity to hERG. The second part describes molecular modeling of hERG’s pore domain. The transmembrane region was modeled after the crystal structure of KvAP pore domain. The S5-P linker was docked to the transmembrane region based on data from previous NMR and mutagenesis experiments, as well as a set of modeling criteria. The models were further restrained by contact points between hERG’s outer vestibule and the bound BeKm-1 toxin molecule deduced from the mutant cycle analysis. Based on these analyses, we propose a working model for the open conformation of the outer vestibule of the hERG channel, in which the S5-P linkers interact with the pore loops to influence ion flux through the pore.


From The Biophysical Journal, Tseng, G-N, Sonawane, K.D., Korolkova, Y.V., et al., Probing the Outer Mouth Structure of the hERG Channel with Peptide Toxin Footprinting and Molecular Modeling, Vol. 92, Page 3524. Copyright © 2007 The Biophysical Society. Published by Elsevier Inc. Reprinted with permission.

Is Part Of

VCU Physiology and Biophysics Publications

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