6CIV

Lactam cyclised mimetic of a fragment of p21

Summary for 6CIV

• Entry DOI: 10.2210/pdb6civ/pdb
• Related: 6CEJ 6CIX
• NMR Information: BMRB: 30414
• Descriptor: p21 (1 entity in total)
• Functional Keywords: pip-box motif, p21, constrained, peptidomimetic, biosynthetic protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 1801.06

Authors

Wegener, K.L. (deposition date: 2018-02-25, release date: 2018-07-04, Last modification date: 2024-10-23)

Primary citation

Wegener, K.L.,McGrath, A.E.,Dixon, N.E.,Oakley, A.J.,Scanlon, D.B.,Abell, A.D.,Bruning, J.B.
Rational Design of a 310-Helical PIP-Box Mimetic Targeting PCNA, the Human Sliding Clamp.
Chemistry, 24:11325-11331, 2018

PubMed Abstract: The human sliding clamp (PCNA) controls access to DNA for many proteins involved in DNA replication and repair. Proteins are recruited to the PCNA surface by means of a short, conserved peptide motif known as the PCNA-interacting protein box (PIP-box). Inhibitors of these essential protein-protein interactions may be useful as cancer therapeutics by disrupting DNA replication and repair in these highly proliferative cells. PIP-box peptide mimetics have been identified as a potentially rapid route to potent PCNA inhibitors. Here we describe the rational design and synthesis of the first PCNA peptidomimetic ligands, based on the high affinity PIP-box sequence from the natural PCNA inhibitor p21. These mimetics incorporate covalent i,i+4 side-chain/side-chain lactam linkages of different lengths, designed to constrain the peptides into the 3 -helical structure required for PCNA binding. NMR studies confirmed that while the unmodified p21 peptide had little defined structure in solution, mimetic ACR2 pre-organized into 3 -helical structure prior to interaction with PCNA. ACR2 displayed higher affinity binding than most known PIP-box peptides, and retains the native PCNA binding mode, as observed in the co-crystal structure of ACR2 bound to PCNA. This study offers a promising new strategy for PCNA inhibitor design for use as anti-cancer therapeutics.

PubMed: 29917264
DOI: 10.1002/chem.201801734

Experimental method

SOLUTION NMR