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  • Combined x-ray and NMR analysis of the stability of the cyclotide cystine knot fold that underpins its insecticidal activity and potential use as a drug scaffold

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    Author
    Wang, Conan K.
    Hu, Shu-Hong
    Martin, Jennifer L.
    Sjogren, Tove
    Hajdu, Janos
    Bohlin, Lars
    Claeson, Per
    Goransson, Ulf
    Rosengren, K. Johan
    Tang, Jun
    Tan, Ninghua
    Craik, David J.
    Year published
    2009
    Metadata
    Show full item record
    Abstract
    Cyclotides are a family of plant defense proteins that are highly resistant to adverse chemical, thermal, and enzymatic treatment. Here, we present the first crystal structure of a cyclotide, varv F, from the European field pansy, Viola arvensis, determined at a resolution of 1.8 Å. The solution state NMR structure was also determined and, combined with measurements of biophysical parameters for several cyclotides, provided an insight into the structural features that account for the remarkable stability of the cyclotide family. The x-ray data confirm the cystine knot topology and the circular backbone, and delineate a conserved network of hydrogen bonds that contribute to the stability of the cyclotide fold. The structural role of a highly conserved Glu residue that has been shown to regulate cyclotide function was also determined, verifying its involvement in a stabilizing hydrogen bond network. We also demonstrate that varv F binds to dodecylphosphocholine micelles, defining the binding orientation and showing that its structure remains unchanged upon binding, further demonstrating that the cyclotide fold is rigid. This study provides a biological insight into the mechanism by which cyclotides maintain their native activity in the unfavorable environment of predator insect guts. It also provides a structural basis for explaining how a cluster of residues important for bioactivity may be involved in self-association interactions in membranes. As well as being important for their bioactivity, the structural rigidity of cyclotides makes them very suitable as a stable template for peptide-based drug design.
    Journal Title
    Journal of Biological Chemistry
    Volume
    284
    Issue
    16
    DOI
    https://doi.org/10.1074/jbc.M900021200
    Copyright Statement
    This research was originally published in Journal of Biological Chemistry (JBC). Conan K. Wang et al, Combined X-ray and NMR Analysis of the Stability of the Cyclotide Cystine Knot Fold That Underpins Its Insecticidal Activity and Potential Use as a Drug Scaffold, Journal of Biological Chemistry (JBC), 284 (16), 10672-10683, 2009. Copyright the American Society for Biochemistry and Molecular Biology. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive version.
    Subject
    Biochemistry and Cell Biology not elsewhere classified
    Publication URI
    http://hdl.handle.net/10072/347142
    Collection
    • Journal articles

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