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

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

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...

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Bibliographic Details
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
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Institution: Nanyang Technological University
Language: English
Description
Summary: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.

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