Molecular mimicry-based repositioning of Nutlin-3 to anti-apoptotic Bcl-2 family proteins

• Main Authors: Ha, Ji-Hyang, Won, Eun-Young, Shin, Jae-Sun, Jang, Mi, Ryu, Kyoung-Seok, Baek, Kwanghee, Park, Sung Goo, Park, Byoung Chul, Yoon, Ho Sup, Chi, Seung-Wook
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2012
• Subjects: DRNTU::Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/79957; http://hdl.handle.net/10220/8736
• Institution: Nanyang Technological University

The identification of off-target binding of drugs is a key to repositioning drugs to new therapeutic categories. Here we show the universal interactions of the p53 transactivation domain (p53TAD) with various antiapoptotic Bcl-2 family proteins via a mouse double minute 2 (MDM2) binding motif, which play an important role in transcription-independent apoptotic pathways of p53. Interestingly, our structural studies reveal that the anti-apoptotic Bcl-2 family proteins and MDM2 share a similar mode of interaction with the p53TAD. On the basis of this close molecular mimicry, our NMR results demonstrate that the potent MDM2 antagonists Nutlin-3 and PMI bind to the anti-apoptotic Bcl-2 family proteins in a manner analogous to that with the p53TAD.