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

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Title
Probing the small-molecule inhibition of an anticancer therapeutic protein-protein interaction using a solid-state nanopore
Author(s)
Dongkyu Kwak; H Chae; Mi-Kyung Lee; Ji-Hyang Ha; G Goyal; M J Kim; K B Kim; Seung-Wook Chi
Bibliographic Citation
Angewandte Chemie-International Edition, vol. 55, pp. 5713-5717
Publication Year
2016
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.
Keyword
drug screeningMDM2p53protein-protein interactionssolid-state nanopores
ISSN
1433-7851
Publisher
Wiley
DOI
http://dx.doi.org/10.1002/anie.201511601
Type
Article
Appears in Collections:
Critical Diseases Diagnostics Convergence Research Center > 1. Journal Articles
Division of Biomedical Research > 1. Journal Articles
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