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PDBsum entry 2nd8
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Lipid binding protein
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PDB id
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2nd8
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References listed in PDB file
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Key reference
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Title
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Structural elucidation of the cell-Penetrating penetratin peptide in model membranes at the atomic level: probing hydrophobic interactions in the blood-Brain barrier.
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Authors
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S.Bera,
R.K.Kar,
S.Mondal,
K.Pahan,
A.Bhunia.
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Ref.
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Biochemistry, 2016,
55,
4982-4996.
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PubMed id
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Abstract
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Cell-penetrating peptides (CPPs) have shown promise in nonpermeable therapeutic
drug delivery, because of their ability to transport a variety of cargo
molecules across the cell membranes and their noncytotoxicity. Drosophila
antennapedia homeodomain-derived CPP penetratin (RQIKIWFQNRRMKWKK), being rich
in positively charged residues, has been increasingly used as a potential drug
carrier for various purposes. Penetratin can breach the tight endothelial
network known as the blood-brain barrier (BBB), permitting treatment of several
neurodegenerative maladies, including Alzheimer's disease, Parkinson's disease,
and Huntington's disease. However, a detailed structural understanding of
penetratin and its mechanism of action is lacking. This study defines structural
features of the penetratin-derived peptide, DK17 (DRQIKIWFQNRRMKWKK), in several
model membranes and describes a membrane-induced conformational transition of
the DK17 peptide in these environments. A series of biophysical experiments,
including high-resolution nuclear magnetic resonance spectroscopy, provides the
three-dimensional structure of DK17 in different membranes mimicking the BBB or
total brain lipid extract. Molecular dynamics simulations support the
experimental results showing preferential binding of DK17 to particular lipids
at atomic resolution. The peptide conserves the structure of the subdomain
spanning residues Ile6-Arg11, despite considerable conformational variation in
different membrane models. In vivo data suggest that the wild type, not a
mutated sequence, enters the central nervous system. Together, these data
highlight important structural and functional attributes of DK17 that could be
utilized in drug delivery for neurodegenerative disorders.
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