Cyclotide Structure

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The structure of circulin A is very similar to that of the other cyclotides.

Stereo view of the backbone residues of 12 NMR derived structures.

Structure of MCoTI-II superimposed over the fruit of M. cochinchinensis. MCotI-II is found in this fruit and acts as a trypsin inhibitor.

3D structure of cycloviolacin O1 showing the alpha-helix in Loop Six.
The three-dimensional structures of four members of the cyclotide family (kalata B1 (Saether, et al., 1995), circulin A (Daly, et al., 1999a), cycloviolacin O1 (Craik, et al., 1999)) and MCoTI-II (Felizmenio-Quimio, et al., 2001, Heitz, et al., 2001)) have been determined by NMR spectroscopy and reveal similar overall folds (Craik, et al., 1999).

The core structural motif has been termed the cyclic cystine knot (CCK) and is characterized by a cystine knot embedded in a macrocyclic backbone (Craik, et al., 1999). The cystine knot involves two intracysteine backbone segments and their connecting disulfide bonds, CysI-CysIV and CysII-CysV, which form a ring that is penetrated by the third disulfide bond, CysIII-CysVI.

The conserved structural characteristics of the cyclotides also include a beta-hairpin, which is generally part of a triple-stranded beta-sheet (Craik, et al., 1999). The third strand is distorted from ideal beta geometry and contains a beta-bulge. The three-dimensional structure of kalata B1 is shown below.

The structure of kalata B1 showing the distorted beta-sheet topology and the loop nomenclature enabled by the cyclic backbone.
Our recent determination of the three-dimensional structure of the 34 residue macrocyclic trypsin inhibitor MCoTI-II from M. cochinchinensis (Felizmenio-Quimio, et al., 2001) revealed a CCK topology similar to the previously determined cyclotides despite the absence of sequence homology. Because of this topological similarity and the conserved macrocyclic backbone we have classified MCoTI-II as a cyclotide. The most significant structural differences between MCoTI-II and the previously known cyclotides include an increased size of the embedded ring of the cystine knot (11 residues instead of 8) and a more disordered loop 6.


Craik DJ, Daly NL, Bond T and Waine C: Plant cyclotides: A unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. J. Mol. Biol. (1999) 294:1327-1336.

Heitz A, Hernandez JF, Gagnon J, Hong TT, Pham TT, Nguyen TM, Le-Nguyen D and Chiche L: Solution structure of the squash trypsin inhibitor MCoTI-II. A new family for cyclic knottins. Biochemistry (2001) 40:7973-7983.

Felizmenio-Quimio M E, Daly N L, Craik D J: Circular proteins in plants: Solution structure of a novel macrocyclic trypsin inhibitor from Momordica cochinchinensis. J. Biol Chem. (2001) 276, 22875-22882.

Saether O, Craik DJ, Campbell ID, Sletten K, Juul J and Norman DG: Elucidation of the primary and three-dimensional structure of the uterotonic polypeptide kalata B1. Biochemistry (1995) 34:4147-4158.