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PDBsum entry 1f0e
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Antimicrobial protein
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PDB id
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1f0e
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References listed in PDB file
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Key reference
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Title
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Role of the hinge region and the tryptophan residue in the synthetic antimicrobial peptides, Cecropin a(1-8)-Magainin 2(1-12) and its analogues, On their antibiotic activities and structures.
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Authors
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D.Oh,
S.Y.Shin,
S.Lee,
J.H.Kang,
S.D.Kim,
P.D.Ryu,
K.S.Hahm,
Y.Kim.
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Ref.
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Biochemistry, 2000,
39,
11855-11864.
[DOI no: ]
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PubMed id
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Abstract
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A 20-residue hybrid peptide CA(1-8)-MA(1-12) (CA-MA), incorporating residues 1-8
of cecropin A (CA) and residues 1-12 of magainin 2 (MA), has potent
antimicrobial activity without toxicity against human erythrocytes. To
investigate the effects of the Gly-Ile-Gly hinge sequence of CA-MA on the
antibacterial and antitumor activities, two analogues in which the Gly-Ile-Gly
sequence of CA-MA is either deleted (P1) or substituted with Pro (P2) were
synthesized. The role of the tryptophan residue at position 2 of CA-MA on its
antibiotic activity was also investigated using two analogues, in which the Trp2
residue of CA-MA is replaced with either Ala (P3) or Leu (P4). The tertiary
structures of CA-MA, P2, and P4 in DPC micelles, as determined by NMR
spectroscopy, have a short amphiphilic helix in the N-terminus and about three
turns of alpha-helix in the C-terminus, with the flexible hinge region between
them. The P1 analogue has an alpha-helix from Leu4 to Ala14 without any hinge
structure. P1 has significantly decreased lytic activities against bacterial and
tumor cells and PC/PS vesicles (3:1, w/w), and reduced pore-forming activity on
lipid bilayers, while P2 retained effective lytic activities and pore-forming
activity. The N-terminal region of P3 has a flexible structure without any
specific secondary structure. The P3 modification caused a drastic decrease in
the antibiotic activities, whereas P4, with the hydrophobic Leu side chain at
position 2, retained its activities. On the basis of the tertiary structures,
antibiotic activities, vesicle-disrupting activities, and pore-forming
activities, the structure-function relationships can be summarized as follows.
The partial insertion of the Trp2 of CA-MA into the membrane, as well as the
electrostatic interactions between the positively charged Lys residues at the
N-terminus of the CA-MA and the anionic phospholipid headgroups, leads to the
primary binding to the cell membrane. Then, the flexibility or bending potential
induced by the Gly-Ile-Gly hinge sequence or the Pro residue in the central part
of the peptides may allow the alpha-helix in the C-terminus to span the lipid
bilayer. These structural features are crucial for the potent antibiotic
activities of CA-MA.
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