Structure-Based Screening Reveals a Ligand That Stabilizes the [2Fe-2S] Clusters of Human mitoNEET and Reduces Ovarian Cancer Cell Proliferation

Human NEET proteins play an important role in a variety of diseases, including cancer. Using the recently published X-ray structure of the human mNT-M1 complex, we screened a commercial chemical compound library and identified a new human mitoNEET (mNT) binding ligand (NTS-01). Biochemical investiga...

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Published in:The journal of physical chemistry. B 2022-11, Vol.126 (46), p.9559-9565
Main Authors: Marjault, Henri-Baptiste, Yang-Sung, Sohn, Zuo, Ke, Carloni, Paolo, Mittler, Ron, Nechushtai, Rachel
Format: Article
Language:English
Subjects:
B: Biophysical and Biochemical Systems and Processes
Cell Proliferation
Early Detection of Cancer
Female
Humans
Iron-Sulfur Proteins - chemistry
Ligands
Mitochondrial Proteins - chemistry
Ovarian Neoplasms - drug therapy
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Summary:Human NEET proteins play an important role in a variety of diseases, including cancer. Using the recently published X-ray structure of the human mNT-M1 complex, we screened a commercial chemical compound library and identified a new human mitoNEET (mNT) binding ligand (NTS-01). Biochemical investigations revealed that NTS-01 specifically binds to the human mNT protein and stabilizes its [2Fe-2S] clusters under oxidative conditions in vitro. Treatment of ovarian cancer cells with NTS-01 induces ovarian cancer (SKOV-3) mitochondrial fragmentation (fission) and reduces ovarian cancer cell proliferation in a 2D single-layer cell culture, as well as in a 3D-spheroids culture. The NTS-01 molecule represents therefore a new lead compound for further drug design studies attempting to develop efficient treatment against ovarian cancer.
ISSN:1520-6106
1520-5207
DOI:10.1021/acs.jpcb.2c05728