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Title 

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

Authors 

Jae-Sun ShinJi-Hyang HaF HeY MutoK S RyuH S YoonSunghyun KangSung Goo ParkByoung Chul ParkS U ChoiSeung-Wook Chi

Publisher 

Elsevier

Issue Date 

2012

Citation 

Biochemical and Biophysical Research Communications, vol. 420, no. 1, pp. 48-53

Keywords 

ApoptosisBcl-2 family proteinsMulti-targeting drugNMRNutlin-3

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.

ISSN 

0006-291X

Link 

http://dx.doi.org/10.1016/j.bbrc.2012.02.113

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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