Key result
Strong blockers that induce >80% irreversible inhibition of current react with channel cysteines much more rapidly than weak blockers and with multiexponential kinetics.
Strong blockers concentrate their maleimide end near the channel's cysteine target by exploiting the reversible pore-blocking affinity of the QA headgroup, accelerating tethering kinetics.
May guide design of irreversible K+ channel inhibitors in models; leaves open translation to mammalian channels or therapy.
Polymeric maleimido-quaternary ammonium (QA) compounds have been shown to function as molecular tape measures when covalently tethered to external cysteine residues of a Shaker K(+) channel (Blaustein R.O., P.A. Cole, C. Williams, and C. Miller. 2000. Nat. Struct. Biol. 7:309-311). For sufficiently long compounds, the cysteine-maleimide tethering reaction creates a high concentration, at the channel's pore, of a TEA-like moiety that irreversibly blocks current. This paper investigates a striking feature of the maleimide-cysteine tethering kinetics. Strong blockers-those that induce substantial levels (>80%) of irreversible inhibition of current-react with channel cysteines much more rapidly than weak blockers and, when delivered to channels with four cysteine targets, react with multiexponential kinetics. This behavior is shown to arise from the ability of a strong blocker to concentrate its maleimide end near a channel's cysteine target by exploiting the reversible pore-blocking affinity of its QA headgroup.
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Robert O. Blaustein (2002) studied this question. Polymeric maleimido-quaternary ammonium (QA) compounds vs. Weak blockers was evaluated on Kinetics of maleimide-cysteine tethering. Strong blockers that induce >80% irreversible inhibition of current react with channel cysteines much more rapidly than weak blockers and with multiexponential kinetics.
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