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

The Journal of Physical Chemistry B, vol. 126, pp. 9559–9565

Abstract

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.

Authors 6

1. Henri‐Baptiste Marjault Aachen Department of Physics

   Hebrew University of Jerusalem · RWTH Aachen University

   Affiliation as printed

   Department of Physics, RWTH Aachen University, 52074Aachen, Germany

   The Alexander Silberman Institute of Life Science and The Wolfson Centre for Applied Structural Biology, Faculty of Science and Mathematics, The Edmond J. Safra Campus at Givat Ram, The Hebrew University of Jerusalem, Jerusalem91904, Israel

2. Yang‐Sung Sohn

   Hebrew University of Jerusalem

   Affiliation as printed

   The Alexander Silberman Institute of Life Science and The Wolfson Centre for Applied Structural Biology, Faculty of Science and Mathematics, The Edmond J. Safra Campus at Givat Ram, The Hebrew University of Jerusalem, Jerusalem91904, Israel

3. Ke Zuo Aachen Department of Physics

   Hebrew University of Jerusalem · RWTH Aachen University

   Affiliation as printed

   Department of Physics, RWTH Aachen University, 52074Aachen, Germany

   The Alexander Silberman Institute of Life Science and The Wolfson Centre for Applied Structural Biology, Faculty of Science and Mathematics, The Edmond J. Safra Campus at Givat Ram, The Hebrew University of Jerusalem, Jerusalem91904, Israel

4. Paolo Carloni Aachen Department of Physics

   Forschungszentrum Jülich · Jülich Aachen Research Alliance · RWTH Aachen University

   Affiliation as printed

   Computational Biomedicine Section, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52425Jülich, Germany

   Computational Biomedicine, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52425Jülich, Germany

   Department of Physics, RWTH Aachen University, 52074Aachen, Germany

   JARA Institute: Molecular Neuroscience and Imaging, Institute of Neuroscience and Medicine INM-11, Forschungszentrum Jülich GmbH, 52425Jülich, Germany

5. Ron Mittler

   University of Missouri

   Affiliation as printed

   Department of Surgery, University of Missouri School of Medicine, and Interdisciplinary Plant Group, Christopher S. Bond Life Sciences Center, University of Missouri, 1201 Rollins Street, Columbia, Missouri65211, United States

6. Rachel Nechushtai corresponding

   Hebrew University of Jerusalem

   Affiliation as printed

   The Alexander Silberman Institute of Life Science and The Wolfson Centre for Applied Structural Biology, Faculty of Science and Mathematics, The Edmond J. Safra Campus at Givat Ram, The Hebrew University of Jerusalem, Jerusalem91904, Israel