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PDBsum entry 2jue
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Antibiotic, plant protein
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PDB id
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2jue
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References listed in PDB file
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Key reference
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Title
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A synthetic mirror image of kalata b1 reveals that cyclotide activity is independent of a protein receptor.
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Authors
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L.Sando,
S.T.Henriques,
F.Foley,
S.M.Simonsen,
N.L.Daly,
K.N.Hall,
K.R.Gustafson,
M.I.Aguilar,
D.J.Craik.
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Ref.
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Chembiochem, 2011,
12,
2456-2462.
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PubMed id
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Abstract
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Featuring a circular, knotted structure and diverse bioactivities, cyclotides
are a fascinating family of peptides that have inspired applications in drug
design. Most likely evolved to protect plants against pests and herbivores,
cyclotides also exhibit anti-cancer, anti-HIV, and hemolytic activities. In all
of these activities, cell membranes appear to play an important role. However,
the question of whether the activity of cyclotides depends on the recognition of
chiral receptors or is primarily modulated by the lipid-bilayer environment has
remained unknown. To determine the importance of lipid membranes on the activity
of the prototypic cyclotide, kalata B1, we synthesized its all-D enantiomer and
assessed its bioactivities. After the all-D enantiomer had been confirmed by
(1)H NMR to be the structural mirror image of the native kalata B1, it was
tested for anti-HIV activity, cytotoxicity, and hemolytic properties. The all-D
peptide is active in these assays, albeit with less efficiency; this reveals
that kalata B1 does not require chiral recognition to be active. The lower
activity than the native peptide correlates with a lower affinity for
phospholipid bilayers in model membranes. These results exclude a chiral
receptor mechanism and support the idea that interaction with phospholipid
membranes plays a role in the activity of kalata B1. In addition, studies with
mixtures of L and D enantiomers of kalata B1 suggested that biological activity
depends on peptide oligomerization at the membrane surface, which determines
affinity for membranes by modulating the association-dissociation equilibrium.
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