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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A structural link between inactivation and block of a K⁺ channel. / Ader, Christian; Schneider, Robert; Hornig, Sönke; Velisetty, Phanindra; Wilson, Erica M.; Lange, Adam; Giller, Karin; Ohmert, Iris; Martin-Eauclaire, Marie France; Trauner, Dirk; Becker, Stefan; Pongs, Olaf; Baldus, Marc.

In: Nature Structural and Molecular Biology, Vol. 15, No. 6, 06.2008, p. 605-612.

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

Ader, Christian ; Schneider, Robert ; Hornig, Sönke ; Velisetty, Phanindra ; Wilson, Erica M. ; Lange, Adam ; Giller, Karin ; Ohmert, Iris ; Martin-Eauclaire, Marie France ; Trauner, Dirk ; Becker, Stefan ; Pongs, Olaf ; Baldus, Marc. / A structural link between inactivation and block of a K⁺ channel. In: Nature Structural and Molecular Biology. 2008 ; Vol. 15, No. 6. pp. 605-612.

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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.",

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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

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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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