Solution structure of BmKTX, a K+ blocker toxin from the Chinese scorpionButhus Martensi

Abstract

BmKTX is a toxin recently purified from the venom of Buthus Martensi, which belongs to the kaliotoxin family. We have determined its solution structure by use of conventional two-dimensional NMR techniques followed by distance-geometry and energy minimization. The calculated structure is composed of a short alpha-helix (residues 14 to 20) connected by a tight turn to a two-stranded antiparallel beta-sheet (sequences 25-27 and 32-34). The beta-turn connecting these strands belongs to type I. The N-terminal segment (sequence 1 to 8) runs parallel to the beta-sheet although it cannot be considered as a third strand. Comparison of the conformation of BmKTX and toxins of the kaliotoxin family clearly demonstrates that they are highly related. Therefore, analysis of the residues belonging to the interacting surface of those toxins allows us to propose a functional map of BmKTX slightly different from the one of KTX and AgTX2, which may explain the variations in affinities of these toxins towards the Kv1.3 channels.

Crystal structure of Natratoxin, a novel snake secreted phospholipaseA2 neurotoxin from Naja atra venom inhibiting A‐type K+ currents

“…It is now clear that K v channel can be targeted by toxins possessing unrelated folds. It has been reported that animal peptide toxins acting as K + channel inhibitors have different structural organizations including Csαβ (cystine stabilized alpha/beta motif) in scorpion toxins, ICK (Inhibitor Cystine Knot) in spider toxins and a short α‐helix without β‐sheet in bee toxins 52, 53. The ability of structurally divergent toxins to recognize a particular ion channel relies on the equivalent spatial distributions of amino acids that are key to the toxin‐channel interaction 17.…”

“…The ability of structurally divergent toxins to recognize a particular ion channel relies on the equivalent spatial distributions of amino acids that are key to the toxin‐channel interaction 17. Previous studies reveal that two protruding basic residues (a lysine and an arginine) serving as crucial residues'an asparagine, a methionine/isoleucine and an aromatic residue acting as influential residues are found in functional sites of all K + channel inhibitors, and this putative functional surface can be considered as the signature motif 52, 53. To detail the molecular basis of the intimate interaction between Natratoxin and I A channel, we compared its structure with other K v channel inhibitors.…”

Scorpion venom components as potential candidates for drug development

“…Another potent and highly selective inhibitor of Kv1.3 is the peptide ADWX-1 (IC 50 of 1.89 pM) which was designed using the structure of BmKTX as template. BmKTX is a peptide isolated from the venom of the scorpion M. martensii Karsch (Renisio et al, 2000). Three non-native mutations were engineered into ADWX-1 (G11R, I28T, and D33H) which increase its affinity 100-fold over the native BmKTX (Kd of 0.2 nM) (Han et al, 2008).…”

α‐Melanophore‐stimulating hormone in the brain, cranial placode derivatives, and retina of Xenopus laevis during development in relation to background adaptation

“…The structure of these toxins consists of a small, triple‐stranded, antiparallel β‐sheet linked to a short helix by two disulfide bridges. An additional (occasionally two) disulfide bond further stabilizes the motif 1–4. The second structural family is characterized by the inhibitor cystine knot (ICK) motif, described as a knot of disulfides (two disulfides and part of the backbone of the protein form a ring, and a third disulfide threads through this ring, leading to the definition of the knot) in the core of the protein 5–7.…”