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Angew. Chem.-Int. Edit., First published: 1 April 2016 | DOI: 10.1002/anie.201511601
Probing the Small-Molecule Inhibition of an Anticancer Therapeutic Protein-Protein Interaction Using a Solid-State Nanopore
Abstract
Dong-Kyu Kwak1,2,†, Hongsik Chae3,†, Dr. Mi-Kyung Lee1,†, Dr. Ji-Hyang Ha1, Dr. Gaurav Goyal4, Prof. Min Jun Kim4,5, Prof. Ki-Bum Kim3,* andDr. Seung-Wook Chi1,2,*
Author Information
1Structural Biology & Nanopore Research Laboratory, Disease Target Structure Research Center, KRIBB, Daejeon, Republic of Korea
2Department of Bio-Analytical Sciences, Korea University of Science and Technology, Daejeon, Republic of Korea
3Department of Materials Science and Engineering, Seoul National University, Seoul, Republic of Korea
4School of Biomedical Engineering, Science and Health Systems Drexel University, Philadelphia, PA, USA
5Department of Mechanical Engineering and Mechanics, Drexel University, Philadelphia, PA, USA
†These authors contributed equally to this work.
*Corresponding authors : Ki-Bum Kim, Seung-Wook Chi
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.
논문정보
- Research article
- 2016년 04월 (BRIC 등록일 2016-04-05)
- 국내(교신)+국외 연구진
- 생명과학 > 구조생물 및 생물물리학
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