E. Katoh et al., Structural basis for the biological activity of dendrotoxin-I, a potent potassium channel blocker, BIOPOLYMERS, 54(1), 2000, pp. 44-57
A topochemical model to explain the biological activity of dendrotoxin-I (D
TX-I), a potent blocker for potassium channels. was developed by searching
common spatial arrangements of functionally important residues between DTX-
I, alpha-dendrotoxin, dendrotoxin-K, BgK, ShK, and charybdotoxin. The first
three are structurally and functionally related to one another and specifi
cally target to Kv1 type potassium channels. The last three are structurall
y unrelated to the first three but have the ability to displace I-125-label
ed dendrotoxins on the same types of potassium channels. In order to obtain
the correct electronic surface potential, thought to be crucial for the DT
X-I function, we determined the three-dimensional solution structure of DTX
-I by nmr spectroscopy using its correct amino acid sequence recently deter
mined by our group. The most interesting characteristic of our model is tha
t DTX-I has two binding sites to potassium channels: one is the cationic do
main made up of Lys residues at positions 5 in the 3(10)-helix, 28 and 29 i
n the beta-turn, and the other is the Lys19/Tyr17/Trp37 triad located in th
e antiprotease dol,lain. The cationic domain and the triad are located at t
he opposite sides of the molecular structure and are separated hy about 25
Angstrom between Lys29 C alpha and Tyr17 C alpha. The functional triad is c
haracterized by three distances, d(1) similar to 7.5 Angstrom (Lys19 C alph
a-the center of the Tyr17 aromatic ring), d(2) similar to 8.1 Angstrom (Lys
19 C alpha-the center of the 6-membered ring of the Trp37 indole group), an
d d(3) similar to 7.3 Angstrom (the center of the the Tyr17 aromatic ring-t
he center of the 6-membered ring of the Trp37 indole group). This model sho
uld aid in the pharmaceutical design of peptide and nonpeptide drugs with p
otassium channel blocking potencies, as well as in understanding of the phy
siology, pharmacology, biochemistry, and structure-function analysis of pot
assium channels. (C) 2000 John Wiley & Sons, Inc. Biopoly 54: 44-57, 2000.