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Proc Natl Acad Sci U S A
2019 Sep 10;11637:18700-18709. doi: 10.1073/pnas.1908903116.
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Pore-modulating toxins exploit inherent slow inactivation to block K+ channels.
Karbat I
,
Altman-Gueta H
,
Fine S
,
Szanto T
,
Hamer-Rogotner S
,
Dym O
,
Frolow F
,
Gordon D
,
Panyi G
,
Gurevitz M
,
Reuveny E
.
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Voltage-dependent potassium channels (Kvs) gate in response to changes in electrical membrane potential by coupling a voltage-sensing module with a K+-selective pore. Animal toxins targeting Kvs are classified as pore blockers, which physically plug the ion conduction pathway, or as gating modifiers, which disrupt voltage sensor movements. A third group of toxins blocks K+ conduction by an unknown mechanism via binding to the channel turrets. Here, we show that Conkunitzin-S1 (Cs1), a peptide toxin isolated from cone snail venom, binds at the turrets of Kv1.2 and targets a network of hydrogen bonds that govern water access to the peripheral cavities that surround the central pore. The resulting ectopic water flow triggers an asymmetric collapse of the pore by a process resembling that of inherent slow inactivation. Pore modulation by animal toxins exposes the peripheral cavity of K+ channels as a novel pharmacological target and provides a rational framework for drug design.
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