Molecular Mimicry-Based Repositioning of Nutlin-3 to Anti-Apoptotic Bcl-2 Family Proteins

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• 作者：Ji-Hyang Ha ; Eun-Young Won ; Jae-Sun Shin ; Mi Jang ; Kyoung-Seok Ryu ; Kwang-Hee Bae ; Sung Goo Park ; Byoung Chul Park ; Ho Sup Yoon ; Seung-Wook Chi
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：February 9, 2011
• 年：2011
• 卷：133
• 期：5
• 页码：1244-1247
• 全文大小：869K
• 年卷期：v.133,no.5(February 9, 2011)
• ISSN：1520-5126

文摘

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 anti-apoptotic 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.