Conduction and block of inward rectifier K+ channels: predicted structure of a potent blocker of Kir2.1.

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.