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PDBsum entry 2e3f
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Antimicrobial protein
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PDB id
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2e3f
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References listed in PDB file
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Key reference
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Title
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Rational design of peptides active against the gram positive bacteria staphylococcus aureus.
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Authors
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C.Landon,
F.Barbault,
M.Legrain,
M.Guenneugues,
F.Vovelle.
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Ref.
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Proteins, 2008,
72,
229-239.
[DOI no: ]
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PubMed id
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Abstract
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In an attempt to increase the antimicrobial activity of the insect defensin from
Anopheles gambiae, which is active against Staphylococcus aureus at low
concentration, hybrid defensins were designed by combining conserved sequence
regions and variable regions of insect defensins. Their activity against S.
aureus strains sensitive and resistant to conventional antibiotics was
evaluated, and the toxicity of the most active molecules was tested. The
three-dimensional structure of Anopheles gambiae defensin and five hybrids were
determined by NMR and molecular modelling. This strategy led to the design of
two chimeric defensins with increased activity compared with the native
molecule, but one of them appears to be toxic to mice at a rather low
concentration. The structure of the CS alphabeta motif, which is a
characteristic of insect defensin, is sensitive to sequence modifications, in
particular in the N-terminal loop. The existence of the CS alphabeta is most
probably a prerequisite for the stability and the activity of the molecule, but
is not sufficient by itself since the hybrid displaying the best defined
structure is not active against the tested strains. The analysis of the
structure, in relation with the activity and the toxicity data, underlines the
importance of turns and of the N-terminal loop. Residues located in the turns
contributing to the preservation of positive electrostatic areas at the surface
of the molecules seem particularly important for the activity of the molecule,
while residues involved in the N-terminal loop are both involved in the
modulation of the activity and the toxicity of the molecule.
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Figure 2.
Figure 2. Superposition of the 10 best models for each hybrid
defensin.
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Figure 3.
Figure 3. Hydrophobic and electrostatic potentials at the
surface of the defensins. First panel: Def-AAA, Def-ABB, and
Def-AcAA; second panel: Def-BAT, Def-BBB, and Def-DAA. Two
orientations are shown. For each orientation, from the left to
the right: the global fold, the hydrophobic potentials and the
electrostatic potentials are represented. For the electrostatic
potential, cationic poles are coloured in red-brown, anionic
regions are in blue, and neutral regions are in green. For the
hydrophobic potential, hydrophobic regions are in brown,
hydrophilic one in blue and intermediate regions are in green.
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The above figures are
reprinted
by permission from John Wiley & Sons, Inc.:
Proteins
(2008,
72,
229-239)
copyright 2008.
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