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Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors

Nature volume 411, pages 657–661 (2001)Cite this article

Abstract

Many voltage-dependent K+ channels open when the membrane is depolarized and then rapidly close by a process called inactivation. Neurons use inactivating K+ channels to modulate their firing frequency. In Shaker-type K+ channels, the inactivation gate, which is responsible for the closing of the channel, is formed by the channel's cytoplasmic amino terminus. Here we show that the central cavity and inner pore of the K+ channel form the receptor site for both the inactivation gate and small-molecule inhibitors. We propose that inactivation occurs by a sequential reaction in which the gate binds initially to the cytoplasmic channel surface and then enters the pore as an extended peptide. This mechanism accounts for the functional properties of K+ channel inactivation and indicates that the cavity may be the site of action for certain drugs that alter cation channel function.

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Figure 1: Biophysical features of K+ channel inactivation.
Figure 2: Mutational analysis of the inactivation gate–receptor interaction.
Figure 3: TBA binds in the cavity of the KcsA K+ channel.
Figure 4: A structural model for the mechanism of inactivation.

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Acknowledgements

We acknowledge the European Synchrotron Radiation Facility (ESRF) and the National Synchrotron Light Source (NSLS) at Brookhaven National Laboratory (with support by the U.S. D.O.E., Division of Material Sciences and Division of Chemical Sciences). We thank C. Petosa and A. Perrakis for help on ESRF ID-13, and M. Becker for help on NSLS X-25. The project was supported by an NIH grant to R.M. R.M. is an investigator in the Howard Hughes Medical Institute.

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Author notes

  1. João H. Morais-Cabral

    Present address: Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, Connecticut, 06520, USA

  2. Roderick MacKinnon: Correspondence and requests for materials should be addressed to R.M.

Authors and Affiliations

  1. Howard Hughes Medical Institute, Laboratory of Molecular Neurobiology and Biophysics, Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Ming Zhou, João H. Morais-Cabral, Sabine Mann & Roderick MacKinnon

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  1. Ming Zhou
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  2. João H. Morais-Cabral
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Corresponding author

Correspondence to Roderick MacKinnon.

Additional information

Coordinates have been deposited with the Protein Data Bank under accession code 1J95.

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Zhou, M., Morais-Cabral, J., Mann, S. et al. Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors. Nature 411, 657–661 (2001). https://doi.org/10.1038/35079500

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