title: Conduction and block of inward rectifier K+ channels: predicted structure of a potent blocker of Kir2.1.
abstract: 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.
authors: Computational Biophysics Group, Research School of Biology, Australian National University , Canberra, ACT 0200, Australia. tamsyn.hilder@anu.edu.au
authors: Tamsyn A
authors: TA
authors: Hilder
authors: Shin-Ho
authors: SH
authors: Chung
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001514:Bee Venoms / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D001516:Bees / Q000737:chemistry / Q000235:genetics; D002645:Chickens; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D001514:Bee Venoms; C489461:Kir2.1 channel; D024661:Potassium Channels, Inwardly Rectifying; C029738:tertiapin