PDBsum entry 1y2p

Toxin

PDB id: 1y2p

Contents

Protein chain

34 a.a.

PDB id:

1y2p

Name:

Toxin

Title:

Solution structure of hstx3p

Structure:

Neurotoxin hstx1. Chain: a. Synonym: hstx3p. Engineered: yes

Source:

Synthetic: yes. Other_details: the peptide was chemically synthesized. Abu19 abu34 of hstx4p

NMR struc:

20 models

Authors:

A.Mosbah,L.Gariga,H.Darbon,J.M.Sabatier

Key ref:

L.Carrega et al. (2005). The impact of the fourth disulfide bridge in scorpion toxins of the alpha-KTx6 subfamily. Proteins, 61, 1010-1023. PubMed id: 16247791 DOI: 10.1002/prot.20681

Date:

23-Nov-04 Release date: 01-Nov-05

Protein chain

P59867  (KAX63_HETSP) -  Potassium channel toxin alpha-KTx 6.3 from Heterometrus spinifer

Seq: 34 a.a.

Struc: 34 a.a.

DOI no: 10.1002/prot.20681

Proteins 61:1010-1023 (2005)

PubMed id: 16247791

The impact of the fourth disulfide bridge in scorpion toxins of the alpha-KTx6 subfamily.

L.Carrega, A.Mosbah, G.Ferrat, C.Beeton, N.Andreotti, P.Mansuelle, H.Darbon, M.De Waard, J.M.Sabatier.

ABSTRACT

Animal toxins are highly reticulated and structured polypeptides that adopt a limited number of folds. In scorpion species, the most represented fold is the alpha/beta scaffold in which an helical structure is connected to an antiparallel beta-sheet by two disulfide bridges. The intimate relationship existing between peptide reticulation and folding remains poorly understood. Here, we investigated the role of disulfide bridging on the 3D structure of HsTx1, a scorpion toxin potently active on Kv1.1 and Kv1.3 channels. This toxin folds along the classical alpha/beta scaffold but belongs to a unique family of short-chain, four disulfide-bridged toxins. Removal of the fourth disulfide bridge of HsTx1 does not affect its helical structure, whereas its two-stranded beta-sheet is altered from a twisted to a nontwisted configuration. This structural change in HsTx1 is accompanied by a marked decrease in Kv1.1 and Kv1.3 current blockage, and by alterations in the toxin to channel molecular contacts. In contrast, a similar removal of the fourth disulfide bridge of Pi1, another scorpion toxin from the same structural family, has no impact on its 3D structure, pharmacology, or channel interaction. These data highlight the importance of disulfide bridging in reaching the correct bioactive conformation of some toxins.

Selected figure(s)

Figure 2.
Figure 2. Three-dimensional structure of [Abu^19,Abu^34]-HsTx1 solved by ^1H-NMR. (A) Amino acid sequence of [Abu^19,Abu^34]-HsTx1 and sequential assignments. X represents the Abu residue that replaces the half-cystine residues. Collected sequential NOEs are classified into strong, medium, and weak NOE, and are indicated by thick, medium, and thin lines, respectively. (B) Stereoviews of the 20 best molecular structures superimposed for best fit. Only backbone atoms are displayed (C[ ], HN, CO) for clarity. (C) Molscript ribbon drawing of the average minimized [Abu^19,Abu^34]-HsTx1 structure. The helix, antiparallel -sheet, C[ ]backbone trace and disulfide bridges are shown in red, blue, yellow, and green, respectively. The six half-cystine residues are indicated with their respective positions.

Figure 4.
Figure 4. Functional maps of HsTx1 and [Abu^19,Abu^34]-HsTx1 for Kv1.1 and Kv1.3 channels. These peptide functional maps were deduced from docking simulation experiments using the 3D structures of HsTx1 and [Abu^19,Abu^34]-HsTx1 and modeled structures of the pore regions of mKv1.1 and mKv1.3 channels. Interacting residues from the Kv channels are shown in red. I to IV before channel residue numbering specifies one of the four -subunits forming the functional Kv channels. Color codes: yellow (hydrophobic residues), light green (polar residues), and blue (basic residues). Swiss-Prot accession codes used are P16388 (mKv1.1) and P16390 (mKv1.3). (A) Functional maps for HsTx1 (left) and [Abu^19,Abu^34]-HsTx1 (right) on Kv1.1. (B) Functional maps for HsTx1 (left) and [Abu^19,Abu^34]-HsTx1 (right) on Kv1.3. The functional maps of both peptides involve mainly their -sheet faces.

The above figures are reprinted by permission from John Wiley & Sons, Inc.: Proteins (2005, 61, 1010-1023) copyright 2005.

Figures were selected by an automated process.