Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1929843 | Biochemical and Biophysical Research Communications | 2012 | 6 Pages |
Multi-targeting therapy is an emerging strategy of drug discovery to improve therapeutic efficacy, safety and resistance profiles. In this study, we monitored the binding of a potent MDM2 inhibitor Nutlin-3 with anti-apoptotic Bcl-2 family proteins using NMR spectroscopy. Our results showed the universal binding of Nutlin-3 with diverse anti-apoptotic Bcl-2 family proteins. Taken together with the binding data for Nutlin-3 analogs, the structural model of the Bcl-XL/Nutlin-3 complex showed that the binding mode of Nutlin-3 resembles that of the Bcl-XL/Bcl-2 inhibitors, suggesting the molecular mechanism of transcription-independent mitochondrial apoptosis by Nutlin-3. Finally, our structural comparison provides structural insights into the dual-targeting mechanism of how Nutlin-3 can bind to two different target proteins, MDM2 and anti-apoptotic Bcl-2 family proteins in a similar manner.
► Universal binding of Nutlin-3 with diverse anti-apoptotic Bcl-2 family proteins. ► Nutlin-3 binds to the BH3 peptide-binding grooves of Bcl-2 family proteins. ► A conserved Bcl-XL binding mechanism of the Nutlin-3 and BH3-mimetic compounds. ► A molecular basis for the transcription-independent apoptosis by Nutlin-3. ► Structural insights into the dual-targeting mechanism of Nutlin-3.