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The Conserved Glu in the Cyclotide Cycloviolacin O2 Has a Key Structural Role
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
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2009 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 10, no 14, 2354-2360 p.Article in journal (Refereed) Published
Abstract [en]

Cyclotides are a large family of plant peptides that are characterised by a head-to-tail circular backbone and three disulfide bonds that are arranged in a cystine knot. This unique structural feature, which is referred to as a cyclic cystine knot, gives the cyclotides remarkable stability against chemical and biological degradation. In addition to their natural function as insecticides for plant defence, the cyclotides have a range of bioactivities with pharmaceutical relevance, including cytotoxicity against cancer cell lines. A glutamic acid residue, aside from the invariable disulfide array, is the most conserved feature throughout the cyclotide family, and it has recently been shown to be crucial for biological activity. Here we have used solution-state NMR spectroscopy to determine the three-dimensional structures of the potent cytotoxic cyclotide cycloviolacin O2, and an inactive analogue in which this conserved glutamic acid has been methylated. The structures of the peptides show that the glutamic acid has a key structural role in coordinating a set of hydrogen bonds in native cycloviolacin O2; this interaction is disrupted in the methylated analogue. The proposed mechanism of action of cyclotides is membrane disruption and these results suggest that the glutamic acid is linked to cyclotide function by stabilising the structure to allow efficient aggregation in membranes, rather than in a direct interaction with a target receptor.

Place, publisher, year, edition, pages
2009. Vol. 10, no 14, 2354-2360 p.
Keyword [en]
cyclotides, cycloviolacin O2, methylation, NMR spectroscopy, peptides, solution structures
National Category
Pharmaceutical Sciences
Research subject
Pharmacognosy
Identifiers
URN: urn:nbn:se:uu:diva-125026DOI: 10.1002/cbic.200900342ISI: 000270401700013OAI: oai:DiVA.org:uu-125026DiVA: diva2:318302
Available from: 2010-05-07 Created: 2010-05-07 Last updated: 2012-01-24Bibliographically approved

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Göransson, Ulf

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