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Much interest has been generated by recent reports on the
discovery of circular (i.e. head-to-tail cyclized) proteins in
plants. Here we report the three-dimensional structure of one of
the newest such circular proteins, MCoTI-II, a novel trypsin
inhibitor from Momordica cochinchinensis, a member of the
Cucurbitacae plant family. The structure consists of a small
beta-sheet, several turns, and a cystine knot arrangement of the
three disulfide bonds. Interestingly, the molecular topology is
similar to that of the plant cyclotides (Craik et al,
1999), which derive from the Rubiaceae and Violaceae plant
families, have antimicrobial activities, and exemplify the cyclic
cystine knot structural motif as part of their circular backbone.
The sequence, biological activity, and plant family of MCoTI-II
are all different from known cyclotides. However, given the
structural similarity, cyclic backbone, and plant origin of
MCoTI-II, we propose that MCoT-II can be classified as a new
member of the cyclotide class of proteins. The expansion of the
cyclotides to include trypsin inhibitory activity and a new plant
family highlights the importance and functional variability of
circular proteins and the fact that they are more common than has
previously been believed. Insights into the possible roles of
backbone cyclization have been gained by a comparison of the
structure of MCoTI-II with the homologous acyclic trypsin
inhibitors CMTI-I and EETI-II from the Cucurbitaceae plant family.
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