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Title 

Probing the small-molecule inhibition of an anticancer therapeutic protein-protein interaction using a solid-state nanopore

Authors 

Dongkyu KwakH ChaeMi-Kyung LeeJi-Hyang HaG GoyalM J KimK B KimSeung-Wook Chi

Publisher 

Wiley-Blackwell

Issue Date 

2016

Citation 

Angewandte Chemie International Edition, vol. 55, no. 0, pp. 5713-5717

Keywords 

drug screeningMDM2p53protein-protein interactionssolid-state nanopores

Abstract 

Nanopore sensing is an emerging technology for the single-molecule-based detection of various biomolecules. In this study, we probed the anticancer therapeutic p53 transactivation domain (p53TAD)/MDM2 interaction and its inhibition with a small-molecule MDM2 antagonist, Nutlin-3, using low-noise solid-state nanopores. Although the translocation of positively charged MDM2 through a nanopore was detected at the applied negative voltage, this MDM2 translocation was almost completely blocked upon formation of the MDM2/GST-p53TAD complex owing to charge conversion. In combination with NMR data, the nanopore measurements showed that the addition of Nutlin-3 rescued MDM2 translocation, indicating that Nutlin-3 disrupted the MDM2/GST-p53TAD complex, thereby releasing MDM2. Taken together, our results reveal that solid-state nanopores can be a valuable platform for the ultrasensitive, picomole-scale screening of small-molecule drugs against protein-protein interaction (PPI) targets.

ISSN 

1433-7851

Link 

http://dx.doi.org/10.1002/anie.201511601

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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