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

• Published in: Biophysical chemistry Vol. 219; pp. 43 - 48
• Main Authors: Li, Daxu, Chen, Rong, Chung, Shin-Ho
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2016
• Subjects: Animals; Bee Venoms - chemistry; Bee Venoms - metabolism; Bees; Binding Sites; G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism; Honey bee toxin; Humans; Kir3.2; Mice; Models, Biological; Molecular dynamics; Molecular Dynamics Simulation; Phosphatidylcholines; Protein Binding; Rats; Sequence Alignment; Substrate Specificity - genetics; Tertiapin; Molecular dynamics; Tertiapin; Kir3.2; Honey bee toxin
• ISSN: 0301-4622; 1873-4200
• DOI: 10.1016/j.bpc.2016.09.010

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 (TPNK16-Kir3.2) or Lys17 (TPNK17-Kir3.2) of the toxin protrudes into the channel pore. However, the binding affinity calculated from only TPNK17-Kir3.2 and not TPNK16-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 TPNK17-Kir3.2, indicating that Kir3.2-Glu127 is important for the selectivity of TPN. [Display omitted] •Tertiapin blocks Kir3.2 by inserting the Lys17 side chain into the channel pore•Glu127 of Kir3.2 is important for tertiapin selectivity.•PMF calculations can help identify the most favorable binding mode.