title: Unique mechanism of the interaction between honey bee toxin TPNQ and rKir1.1 potassium channel explored by computational simulations: insights into the relative insensitivity of channel towards animal toxins.
abstract: BACKGROUND
  The 21-residue compact tertiapin-Q (TPNQ) toxin, a derivative of honey bee toxin tertiapin (TPN), is a potent blocker of inward-rectifier K(+) channel subtype, rat Kir1.1 (rKir1.1) channel, and their interaction mechanism remains unclear.
  
  
  RESULTS
  Based on the flexible feature of potassium channel turrets, a good starting rKir1.1 channel structure was modeled for the accessibility of rKir1.1 channel turrets to TPNQ toxin. In combination with experimental alanine scanning mutagenesis data, computational approaches were further used to obtain a reasonable TPNQ toxin-rKir1.1 channel complex structure, which was completely different from the known binding modes between animal toxins and potassium channels. TPNQ toxin mainly adopted its helical domain as the channel-interacting surface together with His12 as the pore-blocking residue. The important Gln13 residue mainly contacted channel residues near the selectivity filter, and Lys20 residue was surrounded by a polar "groove" formed by Arg118, Thr119, Glu123, and Asn124 in the channel turret. On the other hand, four turrets of rKir1.1 channel gathered to form a narrow pore entryway for TPNQ toxin recognition. The Phe146 and Phe148 residues in the channel pore region formed strong hydrophobic protrusions, and produced dominant nonpolar interactions with toxin residues. These specific structure features of rKir1.1 channel vestibule well matched the binding of potent TPNQ toxin, and likely restricted the binding of the classical animal toxins.
  
  
  CONCLUSIONS
  The TPNQ toxin-rKir1.1 channel complex structure not only revealed their unique interaction mechanism, but also would highlight the diverse animal toxin-potassium channel interactions, and elucidate the relative insensitivity of rKir1.1 channel towards animal toxins.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.forename: Su
authors.initials: S
authors.lastname: Qiu
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Cao
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001514:Bee Venoms / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001516:Bees; D019295:Computational Biology; D004347:Drug Interactions; D004351:Drug Resistance / Q000502:physiology*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000378:metabolism*; D051381:Rats
chemical_list: D001514:Bee Venoms; C510692:Kcnj1 protein, rat; D010446:Peptide Fragments; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; C029738:tertiapin