A pymol movie depicting the complex of MCo-PMI (58 aa) and Hdm2 (129 aa) (PDB code; 2M86).

MCo refers to a cyclotide scaffold derived from a squash "Momordica cochinchinensis". The natural form is called "MCo-TI-I", a trypsin inhibitor (34 aa). The unique structural features of this class of peptide are the head to tail cyclised backbone and 3 interlocking disulfide bonds (cyclic cystein knot) making this structure very stable and highly resistant to proteases.
PMI is a p53 derived helical peptide (12 aa) containing conserved residues crucial for interaction with Hdm2 and Hdmx.
Hdm2 is an E3 ubiquitin ligase that promotes p53 degradation. Hdm2 and Hdmx are upregulatedly expressed in many types of cancer cells.

The engineered cyclotide MCo-PMI was able to bind Hdm2 (and Hdmx) with high affinity (10^-9 M) and unlocked p53 tumor supressor pathway in cancer cells both in vitro and in vivo. MCo-PMI also showed high stability in human serum with the half-life of more than 2 days.

This movie shows the interactions of p53 conserved residues; Phe42, Trp46 and Leu49, of MCo-PMI and the hydrophobic binding cleft of Hdm2, and the salt bridge interaction between Asp35 of MCo-PMI and Lys51 of Hdm2.

Reference:
Ji, Y., Majumder, S., Millard, M., Borra, R., Bi, T., Elnagar, A. Y., . . . Camarero, J. A. (2013).
In Vivo Activation of the p53 Tumor Suppressor Pathway by an Engineered Cyclotide.
Journal of the American Chemical Society, 135(31), 11623-11633.
doi: 10.1021/ja405108p

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