Abstract
Pore-blocking toxins inhibit voltage-dependent K(+) channels (Kv channels) by plugging the ion-conduction pathway. We have solved the crystal structure of paddle chimera, a Kv channel in complex with charybdotoxin (CTX), a pore-blocking toxin. The toxin binds to the extracellular pore entryway without producing discernable alteration of the selectivity filter structure and is oriented to project its Lys27 into the pore. The most extracellular K(+) binding site (S1) is devoid of K(+) electron-density when wild-type CTX is bound, but K(+) density is present to some extent in a Lys27Met mutant. In crystals with Cs(+) replacing K(+), S1 electron-density is present even in the presence of Lys27, a finding compatible with the differential effects of Cs(+) vs K(+) on CTX affinity for the channel. Together, these results show that CTX binds to a K(+) channel in a lock and key manner and interacts directly with conducting ions inside the selectivity filter. DOI:http://dx.doi.org/10.7554/eLife.00594.001.
Highlights
Poisonous animals such as tarantula spiders, green mamba snakes, or the deathstalker scorpion rely on their venom for efficient defense and precapture strategies
Electrophysiological studies of paddle chimera in planar lipid bilayers had revealed that CTX inhibits paddle chimera with high affinity (∼20 nM Kd; Tao and MacKinnon, 2008)
The electron density for the toxin bound to molecule A, referred to as toxin A, was clearer and so we used this map for building a model of the toxin-channel complex
Summary
Poisonous animals such as tarantula spiders, green mamba snakes, or the deathstalker scorpion rely on their venom for efficient defense and precapture strategies. The principal toxic components in all of them are peptidic in nature These venoms usually contain libraries of hundreds of peptide-based toxins that together encompass a high degree of stereochemical diversity (Han et al, 2008; Liang, 2008; Rodriguez de la Vega et al, 2010). A small fraction of these molecules, have been pharmacologically characterized far The targets of these toxins are typically a variety of ion channels—voltage-gated Na+(Nav), K+(Kv), and Ca2+(Cav) channels, and cell-surface ‘receptor’ ion channels, such as the nicotinic acetylcholine (Ach) receptor (Billen et al, 2008; King et al, 2008; Mouhat et al, 2008; Kasheverov et al, 2009). The end result is alteration of the normal physiology of the ion channel/receptor, thereby eliciting the desired reaction of the venom
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