Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 55, Issue 19, Pages 5713-5717Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201511601
Keywords
drug screening; MDM2; p53; protein-protein interactions; solid-state nanopores
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Funding
- National Research Foundation of Korea (NRF) grant - Korean Government (MSIP) [NRF-2012M3C1A3671508]
- Bio-Synergy Research Project of the Ministry of Science, ICT and Future Planning through the National Research Foundation [NRF-2015M3A9C4076320]
- Directorate For Engineering
- Div Of Civil, Mechanical, & Manufact Inn [1435000] Funding Source: National Science Foundation
- National Research Foundation of Korea [2012M3C1A3671508] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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