Molecular dynamics of the honey bee toxin tertiapin binding to Kir3.2

Tertiapin (TPN), a short peptide isolated from the venom of the honey bee, is a potent and selective blocker of the inward rectifier K⁺ (Kir) channel Kir3.2. Here we examine in atomic detail the binding mode of TPN to Kir3.2 using molecular dynamics, and deduce the key residue in Kir3.2 responsible for TPN selectivity. The binding of TPN to Kir3.2 is stable when the side chain of either Lys16 (TPN^K16-Kir3.2) or Lys17 (TPN^K17-Kir3.2) of the toxin protrudes into the channel pore. However, the binding affinity calculated from only TPN^K17-Kir3.2 and not TPN^K16-Kir3.2 is consistent with experiment, suggesting that Lys17 is the most plausible pore-blocking residue. The alanine mutation of Kir3.2-Glu127, which is not present in TPN-resistant channels, reduces the inhibitory ability of TPN by over 50 fold in TPN^K17-Kir3.2, indicating that Kir3.2-Glu127 is important for the selectivity of TPN.

Honey bee toxin; Kir3.2; Molecular dynamics; Tertiapin.