Structural insights into the dual-targeting mechanism of Nutlin-3

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Title
Structural insights into the dual-targeting mechanism of Nutlin-3
Author(s)
Jae-Sun Shin; Ji-Hyang Ha; F He; Y Muto; K S Ryu; H S Yoon; Sunghyun KangSung Goo ParkByoung Chul Park; S U Choi; Seung-Wook Chi
Bibliographic Citation
Biochemical and Biophysical Research Communications, vol. 420, no. 1, pp. 48-53
Publication Year
2012
Abstract
Multi-targeting therapy is an emerging strategy of drug discovery to improve therapeutic efficacy, safety and resistance profiles. In this study, we monitored the binding of a potent MDM2 inhibitor Nutlin-3 with anti-apoptotic Bcl-2 family proteins using NMR spectroscopy. Our results showed the universal binding of Nutlin-3 with diverse anti-apoptotic Bcl-2 family proteins. Taken together with the binding data for Nutlin-3 analogs, the structural model of the Bcl-X L/Nutlin-3 complex showed that the binding mode of Nutlin-3 resembles that of the Bcl-X L/Bcl-2 inhibitors, suggesting the molecular mechanism of transcription-independent mitochondrial apoptosis by Nutlin-3. Finally, our structural comparison provides structural insights into the dual-targeting mechanism of how Nutlin-3 can bind to two different target proteins, MDM2 and anti-apoptotic Bcl-2 family proteins in a similar manner.
Keyword
ApoptosisBcl-2 family proteinsMulti-targeting drugNMRNutlin-3
ISSN
0006-291X
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.bbrc.2012.02.113
Type
Article
Appears in Collections:
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
Division of Biomedical Research > 1. Journal Articles
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