Solution structure of HpTX2, a toxin from Heteropoda venatoria spider thatblocks Kv4.2 potassium channel

HpTX2 is a toxin from the venom of Heteropoda venatoria spider that has bee n demonstrated to bind on Kv4.2 potassium channel. We have determined the s olution structure of recombinant HpTX2 by use of conventional two-dimension al NMR techniques followed by distance-geometry and molecular dynamics. The calculated structure belongs to the Inhibitory Cystin Knot structural fami ly that consists in a compact disulfide-bonded core, from which four loops emerge. A poorly defined two-stranded antiparallel beta -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 desc ribed for kappa -conotoxin PVIIA, but strongly related to the one of charyb dotoxin. 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 t he putative functional surface as well as the lack of an asparagine is prop osed to be the structural basis of the specificity of HpTX2 toward Kv4.2 ch annel.