A structural link between inactivation and block of a K+ channel

Christian Ader; Robert Schneider; Sönke Hornig; Phanindra Velisetty; Erica M. Wilson; Adam Lange; Karin Giller; Iris Ohmert; Marie France Martin-Eauclaire; Dirk Trauner; Stefan Becker; Olaf Pongs; Marc Baldus

doi:10.1038/nsmb.1430

A structural link between inactivation and block of a K⁺ channel

Christian Ader, Robert Schneider, Sönke Hornig, Phanindra Velisetty, Erica M. Wilson, Adam Lange, Karin Giller, Iris Ohmert, Marie France Martin-Eauclaire, Dirk Trauner, Stefan Becker, Olaf Pongs, Marc Baldus

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Gating the ion-permeation pathway in K⁺ channels requires conformational changes in activation and inactivation gates. Here we have investigated the structural alterations associated with pH-dependent inactivation gating of the KcsA-Kv1.3 K⁺ channel using solid-state NMR spectroscopy in direct reference to electrophysiological and pharmacological experiments. Transition of the KcsA-Kv1.3 K⁺ channel from a closed state at pH 7.5 to an inactivated state at pH 4.0 revealed distinct structural changes within the pore, correlated with activation-gate opening and inactivation-gate closing. In the inactivated K⁺ channel, the selectivity filter adopts a nonconductive structure that was also induced by binding of a pore-blocking tetraphenylporphyrin derivative. The results establish a structural link between inactivation and block of a K⁺ channel in a membrane setting.

Original language	English (US)
Pages (from-to)	605-612
Number of pages	8
Journal	Nature Structural and Molecular Biology
Volume	15
Issue number	6
DOIs	https://doi.org/10.1038/nsmb.1430
State	Published - Jun 2008

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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10.1038/nsmb.1430

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title = "A structural link between inactivation and block of a K+ channel",

abstract = "Gating the ion-permeation pathway in K+ channels requires conformational changes in activation and inactivation gates. Here we have investigated the structural alterations associated with pH-dependent inactivation gating of the KcsA-Kv1.3 K+ channel using solid-state NMR spectroscopy in direct reference to electrophysiological and pharmacological experiments. Transition of the KcsA-Kv1.3 K+ channel from a closed state at pH 7.5 to an inactivated state at pH 4.0 revealed distinct structural changes within the pore, correlated with activation-gate opening and inactivation-gate closing. In the inactivated K+ channel, the selectivity filter adopts a nonconductive structure that was also induced by binding of a pore-blocking tetraphenylporphyrin derivative. The results establish a structural link between inactivation and block of a K+ channel in a membrane setting.",

author = "Christian Ader and Robert Schneider and S{\"o}nke Hornig and Phanindra Velisetty and Wilson, {Erica M.} and Adam Lange and Karin Giller and Iris Ohmert and Martin-Eauclaire, {Marie France} and Dirk Trauner and Stefan Becker and Olaf Pongs and Marc Baldus",

note = "Funding Information: Technical assistance by B. Angerstein is gratefully acknowledged. This work was funded in part by the Deutsche Forschungsgemeinschaft (DFG; Ba 1700/9-1, Be 2345/5-1, Po 137/38-1), by a PhD fellowship to C.A. from the Stiftung Stipendien-Fonds of the Verband der Chemischen Industrie, and by a PhD fellowship to R.S. from the DFG graduate school 782 {\textquoteleft}Spectroscopy and Dynamics of Molecular Coils and Aggregates{\textquoteright}. We are indebted to R. Wagner (University of Osnabr{\"u}ck, Germany) for invaluable support in context of the lipid-bilayer reconstitution experiments. We are grateful to R. Riek for providing solution-state NMR resonance assignments of KcsA constructs in micelles.",

year = "2008",

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language = "English (US)",

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AU - Ader, Christian

AU - Schneider, Robert

AU - Hornig, Sönke

AU - Velisetty, Phanindra

AU - Wilson, Erica M.

AU - Lange, Adam

AU - Giller, Karin

AU - Ohmert, Iris

AU - Martin-Eauclaire, Marie France

AU - Trauner, Dirk

AU - Becker, Stefan

AU - Pongs, Olaf

AU - Baldus, Marc

N1 - Funding Information: Technical assistance by B. Angerstein is gratefully acknowledged. This work was funded in part by the Deutsche Forschungsgemeinschaft (DFG; Ba 1700/9-1, Be 2345/5-1, Po 137/38-1), by a PhD fellowship to C.A. from the Stiftung Stipendien-Fonds of the Verband der Chemischen Industrie, and by a PhD fellowship to R.S. from the DFG graduate school 782 ‘Spectroscopy and Dynamics of Molecular Coils and Aggregates’. We are indebted to R. Wagner (University of Osnabrück, Germany) for invaluable support in context of the lipid-bilayer reconstitution experiments. We are grateful to R. Riek for providing solution-state NMR resonance assignments of KcsA constructs in micelles.

PY - 2008/6

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N2 - Gating the ion-permeation pathway in K+ channels requires conformational changes in activation and inactivation gates. Here we have investigated the structural alterations associated with pH-dependent inactivation gating of the KcsA-Kv1.3 K+ channel using solid-state NMR spectroscopy in direct reference to electrophysiological and pharmacological experiments. Transition of the KcsA-Kv1.3 K+ channel from a closed state at pH 7.5 to an inactivated state at pH 4.0 revealed distinct structural changes within the pore, correlated with activation-gate opening and inactivation-gate closing. In the inactivated K+ channel, the selectivity filter adopts a nonconductive structure that was also induced by binding of a pore-blocking tetraphenylporphyrin derivative. The results establish a structural link between inactivation and block of a K+ channel in a membrane setting.

AB - Gating the ion-permeation pathway in K+ channels requires conformational changes in activation and inactivation gates. Here we have investigated the structural alterations associated with pH-dependent inactivation gating of the KcsA-Kv1.3 K+ channel using solid-state NMR spectroscopy in direct reference to electrophysiological and pharmacological experiments. Transition of the KcsA-Kv1.3 K+ channel from a closed state at pH 7.5 to an inactivated state at pH 4.0 revealed distinct structural changes within the pore, correlated with activation-gate opening and inactivation-gate closing. In the inactivated K+ channel, the selectivity filter adopts a nonconductive structure that was also induced by binding of a pore-blocking tetraphenylporphyrin derivative. The results establish a structural link between inactivation and block of a K+ channel in a membrane setting.

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A structural link between inactivation and block of a K⁺ channel

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