I. Krimm et al., NMR structures and activity of a novel alpha-like toxin from the scorpion Leiurus quinquestriatus hebraeus, J MOL BIOL, 285(4), 1999, pp. 1749-1763
NMR structures of a new toxin from the scorpion Leiurus quinquestriatus heb
raeus (Lqh III) have been investigated in conjunction with its pharmacologi
cal properties. This toxin is proposed to belong to a new group of scorpion
toxins, the alpha-like toxins that target voltage-gated sodium channels wi
th specific properties compared with the classical alpha-scorpion toxins. E
lectrophysiological analysis showed that Lqh III inhibits a sodium current
inactivation in the cockroach axon, but induces in addition a resting depol
arization due to a slowly decaying tail current atypical to other alpha-tox
in action. Binding studies indicated that radiolabeled Lqh III binds with a
high degree of affinity (K-i = 2.2 nM) on cockroach sodium channels and th
at the alpha-toxin from L quinquestriatus hebraeus highly active on insects
(Lqh alpha IT) and alpha-like toxins compete at low concentration for its
receptor binding site, suggesting that the alpha-like toxin receptor site i
s partially overlapping with the receptor site 3. Conversely, in rat brain,
Lqh III competes for binding of the most potent anti-mammal alpha-toxin fr
om Androctonus australis Hector venom (AaH II) only at very high concentrat
ion.
The NMR structures were used for the scrutiny of the similarities and diffe
rences with representative scorpion alpha-toxins targeting the voltage-gate
d sodium channels of either mammals or insects. Three turn regions involved
in the functional binding site of the anti-insect Lqh alpha IT toxin revea
l significant differences in the Lqh III structure. The electrostatic charg
e distribution in the Lqh III toxin is also surprisingly different when com
pared with the anti-mammal alpha-toxin AaH II. Similarities in the electros
tatic charge distribution are, however, recognized between alpha-toxins hig
hly active on insects and the alpha-like toxin Lqh III. This affords additi
onal important elements to the definition of the new alpha-like group of sc
orpion toxins and the mammal vel sus insect scorpion toxin selectivities. (
C) 1999 Academic Press.