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Title:
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Molecular mimicry-based repositioning of Nutlin-3 to anti-apoptotic Bcl-2 family proteins.
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Author:
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Ha, Ji-Hyang.; Won, Eun-Young.; Shin, Jae-Sun.; Jang, Mi.; Ryu, Kyoung-Seok.; Bae, Kwang-Hee.; Park, Sung Goo.; Park, Byoung Chul.; Yoon, Ho Sup.; Chi, Seung-Wook.
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Copyright year:
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2011 |
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Abstract:
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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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Subject:
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DRNTU::Science::Biological sciences |
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Type:
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Journal Article |
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Series/ Journal Title:
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Journal of the American chemical society |
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School:
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School of Biological Sciences |
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Rights:
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© 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. |
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Version:
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Accepted version |
