title: 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.affiliation: Medical Proteomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors.forename: Jae-Sun
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Medical Proteomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors.forename: Ji-Hyang
authors.initials: JH
authors.lastname: Ha
authors.affiliation: Medical Proteomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea. Electronic address: swchi@kribb.re.kr.
authors.forename: Seung-Wook
authors.initials: SW
authors.lastname: Chi
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D001665:Binding Sites; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism*; D051020:bcl-X Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Bcl-2 family proteins; Cancer therapy; MDM2; Multi-targeting; NMR spectroscopy; PMI; p53 Peptide analogue; pDI