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Chembiochem. 2019 Jun 27. doi: 10.1002/cbic.201900275. [Epub ahead of print]

Targeting PCNA with peptide mimetics for therapeutic purposes.

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University of Adelaide, Department of Molecular and Biomedical Science, Gate 8 Victoria Drive, MLS Building, 5005, Adelaide, AUSTRALIA.


PCNA is an excellent inhibition target to shut down highly proliferative cells and thereby develop a broad spectrum cancer therapeutic. It interacts with a wide variety of proteins through a conserved motif referred to as the PCNA-Interacting Protein (PIP) box. There is large sequence diversity between high affinity PCNA binding partners, with conservation of the binding structure - a well-defined 310-helix. Here, all current PIP-box peptides crystallised with human PCNA are collated to reveal common trends between binding structure and affinity. Key intra- and inter-molecular hydrogen bonding networks which stabilise the 310-helix of PIP-box partners are highlighted, and related back to the canonical PIP-box motif. High correlation with the canonical PIP-box sequence does not directly afford high affinity. Instead, we summarise key interactions which stabilise the binding structure that lead to enhanced PCNA binding affinity. These interactions also implicate the 'non-conserved' residues within the PIP-box that have previously been overlooked. Such insights will allow a more directed approach to develop therapeutic PCNA inhibitors.


PCNA, peptide mimetics, PIP-box, sliding clamp, DNA replication


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