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Structural basis of TEA blockade in a model potassium channel

Nature Structural & Molecular Biology volume 12, pages 454–459 (2005)Cite this article

Abstract

Potassium channels catalyze the selective transfer of potassium across the cell membrane and are essential for setting the resting potential in cells, controlling heart rate and modulating the firing pattern in neurons. Tetraethylammonium (TEA) blocks ion conduction through potassium channels in a voltage-dependent manner from both sides of the membrane. Here we show the structural basis of TEA blockade by cocrystallizing the prokaryotic potassium channel KcsA with two selective TEA analogs. TEA binding at both sites alters ion occupancy in the selectivity filter; these findings underlie the mutual destabilization and voltage-dependence of TEA blockade. We propose that TEA blocks potassium channels by acting as a potassium analog at the dehydration transition step during permeation.

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Figure 1: Mechanism of permeation in potassium channels.
Figure 2: Structure of the selectivity filter in the presence of TBA.
Figure 3: Structure of the selectivity filter in the presence of TEAs.
Figure 4: Mechanism of TEA blockade.

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Acknowledgements

We thank J. Cieslak, D. Freymann, C. LaBonne, K. Swartz and J. Yeh for critical reading of the manuscript, and Z. Wawrzak for assistance with data collection. This work was supported by US National Institutes of Health grant GM58568 to A.G. Support from the R.H. Lurie Comprehensive Cancer Center of Northwestern University to the Structural Biology Facility is acknowledged. DND-CAT is supported by DuPont, Dow, the US National Science Foundation and the State of Illinois. Portions of this work were carried out at BioCARS (sector 14) and the Structural Biology Center (sector 19) at the Advanced Photon Source (APS). Use of the APS is supported by the US Department of Energy (contract W-31-109-Eng-38).

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  1. Michael J Lenaeus and Magdalini Vamvouka: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, 60611, Illinois, USA

    Michael J Lenaeus, Magdalini Vamvouka, Pamela J Focia & Adrian Gross

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  1. Michael J Lenaeus
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Correspondence to Adrian Gross.

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Lenaeus, M., Vamvouka, M., Focia, P. et al. Structural basis of TEA blockade in a model potassium channel. Nat Struct Mol Biol 12, 454–459 (2005). https://doi.org/10.1038/nsmb929

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