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

Abstract

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.

• Authors: Jae-Sun Shin, Ji-Hyang Ha, Seung-Wook Chi
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 443 Issue 3 Pg. 882-7 (Jan 17 2014) ISSN: 1090-2104 [Electronic] United States
• PMID: 24342622 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Peptides
• Proto-Oncogene Proteins c-bcl-2
• Tumor Suppressor Protein p53
• bcl-X Protein
• Proto-Oncogene Proteins c-mdm2

Topics

• Amino Acid Sequence
• Apoptosis
• Binding Sites
• Magnetic Resonance Spectroscopy
• Models, Molecular
• Molecular Sequence Data
• Peptides (chemistry, metabolism)
• Protein Binding
• Protein Interaction Mapping
• Protein Structure, Secondary
• Protein Structure, Tertiary
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Proto-Oncogene Proteins c-mdm2 (chemistry, metabolism)
• Tumor Suppressor Protein p53 (chemistry, metabolism)
• bcl-X Protein (chemistry, metabolism)