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

Cited 38 time in scopus
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Title
Molecular mimicry-based repositioning of nutlin-3 to anti-apoptotic Bcl-2 family proteins
Author(s)
Ji-Hyang Ha; Eunyoung Won; Jae-Sun Shin; M Jang; K S Ryu; Kwang-Hee BaeSung Goo ParkByoung Chul Park; H S Yoon; Seung-Wook Chi
Bibliographic Citation
Journal of American Chemical Society, vol. 133, no. 5, pp. 1244-1247
Publication Year
2011
Abstract
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.
ISSN
0002-7863
Publisher
Amer Chem Soc
DOI
http://dx.doi.org/10.1021/ja109521f
Type
Article
Appears in Collections:
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
Critical Diseases Diagnostics Convergence Research Center > 1. Journal Articles
Division of Biomedical Research > 1. Journal Articles
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