HpTX2 is a toxin from the venom of Heteropoda
venatoria spider that has been demonstrated to bind
on Kv4.2 potassium channel. We have determined the solution
structure of recombinant HpTX2 by use of conventional two-dimensional
NMR techniques followed by distance-geometry and molecular
dynamics. The calculated structure belongs to the Inhibitory
Cystin Knot structural family that consists in a compact
disulfide-bonded core, from which four loops emerge. A
poorly defined two-stranded antiparallel β-sheet (residues
20–23 and 25–28) is detected. Analysis of the
electrostatic charge anisotropy allows us to propose a
functional map of HpTX2 different from the one described
for κ-conotoxin PVIIA, but strongly related to the
one of charybdotoxin. The orientation of the dipole moment
of HpTX2 emerges through K27 which could therefore be the
critical lysine residue. Close to this lysine are a second
basic residue, R23, an aromatic cluster (F7, W25, W30)
and an hydrophobic side chain (L24). The high density in
aromatic side chains of the putative functional surface
as well as the lack of an asparagine is proposed to be
the structural basis of the specificity of HpTX2 toward
Kv4.2 channel.