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Title: Structural insights into the dual-targeting mechanism of Nutlin-3
Authors: Shin, Jae-Sun
Ha, Ji-Hyang
He, Fahu
Muto, Yutaka
Ryu, Kyoung-Seok
Yoon, Ho Sup
Kang, Sunghyun
Park, Sung Goo
Park, Byoung Chul
Choi, Sang-Un
Chi, Seung-Wook
Keywords: DRNTU::Science::Biological sciences
Issue Date: 2012
Source: Shin, J.-S., Ha, J.-H., He, F., Muto, Y., Ryu, K.-S., Yoon, H. S., et al. (2012). Structural insights into the dual-targeting mechanism of Nutlin-3. Biochemical and Biophysical Research Communications, 420(1), 48-53.
Series/Report no.: Biochemical and biophysical research communications
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-XL/Nutlin-3 complex showed that the binding mode of Nutlin-3 resembles that of the Bcl-XL/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
DOI: 10.1016/j.bbrc.2012.02.113
Schools: School of Biological Sciences 
Rights: © 2012 Elsevier lnc.
Fulltext Permission: none
Fulltext Availability: No Fulltext
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