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Title 

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

Authors 

Ji-Hyang HaEunyoung WonJae-Sun ShinM JangK S RyuKwang-Hee BaeSung Goo ParkByoung Chul ParkH S YoonSeung-Wook Chi

Publisher 

American Chemical Society

Issue Date 

2011

Citation 

Journal of American Chemical Society, vol. 133, no. 5, pp. 1244-1247

Keywords 

ApoptoticApoptotic pathwaysBcl-2 family proteinsBinding motifMolecular mimicryMouse double minute 2Structural studiesTarget bindingTransactivation domain

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

Link 

http://dx.doi.org/10.1021/ja109521f

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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