1. The Howard Hughes Medical Institute and Rockefeller University, 1230 York Avenue, New York, New York 10021, USA

Correspondence to: Roderick MacKinnon¹ Email: mackinn@rockefeller.edu

Abstract

Venomous animals produce small protein toxins that inhibit ion channels with high affinity. In several well-studied cases the inhibitory proteins are water-soluble and bind at a channel's aqueous-exposed extracellular surface^{1, 2, 3, 4}. Here we show that a voltage-sensor toxin (VSTX1) from the Chilean Rose Tarantula (Grammostola spatulata) reaches its target by partitioning into the lipid membrane. Lipid membrane partitioning serves two purposes: to localize the toxin in the membrane where the voltage sensor resides and to exploit the free energy of partitioning to achieve apparent high-affinity inhibition. VSTX1, small hydrophobic poisons and anaesthetic molecules reveal a common theme of voltage sensor inhibition through lipid membrane access. The apparent requirement for such access is consistent with the recent proposal that the sensor in voltage-dependent K⁺ channels is located at the membrane–protein interface^{5, 6}.

1. The Howard Hughes Medical Institute and Rockefeller University, 1230 York Avenue, New York, New York 10021, USA

Correspondence to: Roderick MacKinnon¹ Email: mackinn@rockefeller.edu

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