Key result
Single tertiapin-Q mutation increases Kir2.1 channel binding affinity ~187,000-fold.
A single mutation of tertiapin-Q creates a highly potent blocker of Kir2.1 channels (Kd = 0.7 nM), providing a structural template for developing new antiarrhythmic drugs.
Dysfunction of Kir2.1, thought to be the major component of inward currents, I(K1), in the heart, has been linked to various channelopathies, such as short Q-T syndrome. Unfortunately, currently no known blockers of Kir2.x channels exist. In contrast, Kir1.1b, predominantly expressed in the kidney, is potently blocked by an oxidation-resistant mutant of the honey bee toxin tertiapin (tertiapin-Q). Using various computational tools, we show that both channels are closed by a hydrophobic gating mechanism and inward rectification occurs in the absence of divalent cations and polyamines. We then demonstrate that tertiapin-Q binds to the external vestibule of Kir1.1b and Kir2.1 with K(d) values of 11.6 nM and 131 μM, respectively. We find that a single mutation of tertiapin-Q increases the binding affinity for Kir2.1 by 5 orders of magnitude (K(d) = 0.7 nM). This potent blocker of Kir2.1 may serve as a structural template from which potent compounds for the treatment of various diseases mediated by this channel subfamily, such as cardiac arrhythmia, can be developed.
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Hilder et al. (2013) studied Channelopathies (e.g., short Q-T syndrome, cardiac arrhythmia). Tertiapin-Q mutant vs. Tertiapin-Q was evaluated on Binding affinity (Kd) for Kir2.1. A single mutation of tertiapin-Q increased the binding affinity for the Kir2.1 channel by 5 orders of magnitude (Kd = 0.7 nM compared to 131 μM).
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