Targeting of p53 peptide analogues to anti-apoptotic Bcl-2 family proteins as revealed by NMR spectroscopy

• Published in: Biochemical and biophysical research communications Vol. 443; no. 3; pp. 882 - 887
• Main Authors: Shin, Jae-Sun, Ha, Ji-Hyang, Chi, Seung-Wook
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.01.2014
• Subjects: Amino Acid Sequence; Apoptosis; Bcl-2 family proteins; bcl-X Protein - chemistry; bcl-X Protein - metabolism; Binding Sites; Cancer therapy; domain; family; hydrophobicity; Magnetic Resonance Spectroscopy; MDM2; Models, Molecular; Molecular Sequence Data; Multi-targeting; neoplasms; NMR spectroscopy; nuclear magnetic resonance spectroscopy; p53 Peptide analogue; pDI; peptides; Peptides - chemistry; Peptides - metabolism; PMI; Protein Binding; Protein Interaction Mapping; Protein Structure, Secondary; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-mdm2 - chemistry; Proto-Oncogene Proteins c-mdm2 - metabolism; transcriptional activation; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - metabolism; p53 Peptide analogue; pDI; Multi-targeting; Cancer therapy; MDM2; Bcl-2 family proteins; NMR spectroscopy; PMI
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2013.12.054

•Targeting of p53 peptide analogues to anti-apoptotic Bcl-2 family proteins.•PMI and pDI peptides bind to BH3 peptide-binding grooves of Bcl-2 family proteins.•A structural model for the Bcl-XL/PMI peptide complex.•A conserved Bcl-XL binding mode of the PMI and BH3 peptides.•Structural basis for the multi-targeting mechanism of PMI peptide. Inhibition of the interaction between the p53 tumor suppressor and its negative regulator MDM2 is of great importance to cancer therapy. The anti-apoptotic Bcl-2 family proteins are also attractive anti-cancer molecular targets, as they are key regulators of apoptotic cell death. Previously, we reported the interactions between the p53 transactivation domain (p53TAD) and diverse members of the anti-apoptotic Bcl-2 family proteins. In this study, we investigated the binding of MDM2-inhibiting p53TAD peptide analogues, p53-MDM2/MDMX inhibitor (PMI) and pDI, with anti-apoptotic Bcl-2 family proteins, Bcl-XL and Bcl-2, by using NMR spectroscopy. The NMR chemical shift perturbation data demonstrated the direct binding of the p53 peptide analogues to Bcl-XL and Bcl-2 and showed that the PMI and pDI peptides bind to a conserved hydrophobic groove of the anti-apoptotic Bcl-2 family proteins. Furthermore, the structural model of the Bcl-XL/PMI peptide complex showed that the binding mode of the PMI peptide is highly similar to that of pro-apoptotic Bcl-2 homology 3 (BH3) peptides. Finally, our structural comparison provided a molecular basis for how the same PMI peptide can bind to two distinct anti-cancer target proteins Bcl-XL and MDM2, which may have potential applications for multi-targeting cancer therapy.