Molecular mimicry-based repositioning of Nutlin-3 to anti-apoptotic Bcl-2 family proteins
Park, Sung Goo
Park, Byoung Chul
Yoon, Ho Sup
Date of Issue2011
School of Biological Sciences
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.
Journal of the American chemical society
© 2011 American Chemical Society. This is the author created version of a work that has been peer reviewed and accepted for publication by Journal of the American Chemical Society , American Chemical Society. It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: http://dx.doi.org/10.1021/ja109521f.