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PDBsum entry 1y2p
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References listed in PDB file
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Key reference
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Title
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The impact of the fourth disulfide bridge in scorpion toxins of the alpha-Ktx6 subfamily.
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Authors
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L.Carrega,
A.Mosbah,
G.Ferrat,
C.Beeton,
N.Andreotti,
P.Mansuelle,
H.Darbon,
M.De waard,
J.M.Sabatier.
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Ref.
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Proteins, 2005,
61,
1010-1023.
[DOI no: ]
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PubMed id
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Abstract
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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.
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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.
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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.
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The above figures are
reprinted
by permission from John Wiley & Sons, Inc.:
Proteins
(2005,
61,
1010-1023)
copyright 2005.
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