4OWI

peptide structure

Summary for 4OWI

• Entry DOI: 10.2210/pdb4owi/pdb
• Descriptor: p53LZ2 (2 entities in total)
• Functional Keywords: inhibitor, unknown function
• Biological source: synthetic construct
• Total number of polymer chains: 2
• Total formula weight: 7861.36

Authors

Lee, J.-H. (deposition date: 2014-02-02, release date: 2014-05-21, Last modification date: 2023-12-27)

Primary citation

Lee, J.H.,Kang, E.,Lee, J.,Kim, J.,Lee, K.H.,Han, J.,Kang, H.Y.,Ahn, S.,Oh, Y.,Shin, D.,Hur, K.,Chae, S.Y.,Song, P.H.,Kim, Y.I.,Park, J.C.,Lee, J.I.
Protein grafting of p53TAD onto a leucine zipper scaffold generates a potent HDM dual inhibitor.
Nat Commun, 5:3814-3814, 2014

PubMed Abstract: Reactivation of the p53 pathway by a potential therapeutic antagonist, which inhibits HDM2 and HDMX, is an attractive strategy for drug development in oncology. Developing blockers towards conserved hydrophobic pockets of both HDMs has mainly focused on small synthetic compounds; however, this approach has proved challenging. Here we describe an approach to generate a potent HDM dual inhibitor, p53LZ2, by rational protein grafting of the p53 transactivation domain onto a homodimeric leucine zipper. p53LZ2 shows tight binding affinity to both HDMs compared with wild-type p53 in vitro. X-ray crystallographic, comparative modelling and small-angle X-ray scattering studies of p53LZ2-HDM complexes show butterfly-shaped structures. A cell-permeable TAT-p53LZ2 effectively inhibits the cancer cell growth in wild-type but not mutant p53 by arresting cell cycle and inducing apoptosis in vitro. Thus, p53LZ2, designed by rational grafting, shows a potential therapeutic approach against cancer.

PubMed: 24804811
DOI: 10.1038/ncomms4814

Experimental method

X-RAY DIFFRACTION (1.202 Å)