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Probing the Small‐Molecule Inhibition of an Anticancer Therapeutic Protein‐Protein Interaction Using a Solid‐State Nanopore
Author(s) -
Kwak DongKyu,
Chae Hongsik,
Lee MiKyung,
Ha JiHyang,
Goyal Gaurav,
Kim Min Jun,
Kim KiBum,
Chi SeungWook
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201511601
Subject(s) - nanopore , mdm2 , small molecule , transactivation , biomolecule , chromosomal translocation , biophysics , molecule , chemistry , nanotechnology , solid state , materials science , biochemistry , biology , transcription factor , organic chemistry , gene
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.