Targeting PCNA with peptide mimetics for therapeutic purposes
Date
2020
Authors
Horsfall, A.J.
Abell, A.D.
Bruning, J.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
ChemBioChem: a European journal of chemical biology, 2020; 21(4):442-450
Statement of Responsibility
Aimee J. Horsfall, Andrew D. Abell and John B. Bruning
Conference Name
Abstract
Proliferating cell nuclear antigen (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, but with conservation of the binding structure - a well‐defined 3₁₀‐helix. Herein, all current PIP‐box peptides crystallised with human PCNA are collated to reveal common trends between binding structure and affinity. Key intra‐ and intermolecular hydrogen‐bonding networks that 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 that stabilise the binding structure that leads 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.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim