Structural insights into the dual-targeting mechanism of Nutlin-3

• Main Authors: Shin, Jae-Sun, Ha, Ji-Hyang, He, Fahu, Muto, Yutaka, Ryu, Kyoung-Seok, Yoon, Ho Sup, Kang, Sunghyun, Park, Sung Goo, Park, Byoung Chul, Choi, Sang-Un, Chi, Seung-Wook
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2013
• Subjects: DRNTU::Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/99837; http://hdl.handle.net/10220/11029
• Institution: Nanyang Technological University

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.