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NMR Screening of mSin3B Binding Compounds for the Interaction Inhibition with a Neural Repressor, NRSF/REST

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Modern Magnetic Resonance

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Abstract

A neuron-restrictive silencer factor (NRSF/REST) binds to neural restrictive silencing element found in almost all neuronal genes and recruits corepressors to inhibit the neuronal gene expression in non-neuronal cells and neuron progenitor cells. One of the corepressors, mSin3, contains four paired amphipathic helix (PAH) domains, PAH1–PAH4, and the PAH1 domain binds to the repressor domain of NRSF/REST. Dysregulation of NRSF/REST is related to severe neurological diseases, for example, Huntington’s disease, medulloblastoma, and neuropathic pains. Inhibitor compounds, which bind to the NRSF/REST binding site of the PAH1 domain and inhibit the binding of NRSF/REST, are likely drug candidates to recover from these severe neurological diseases. So far, the biochemical and cellular functions of several compounds have been examined related to diseases such as Huntington’s disease, partially based on the complex structure of the NRSF/REST repressor domain bound to the mSin3 PAH1 domain. To design rationally such inhibitor compounds, NMR is one of the most powerful methods. The binding abilities of some compounds to the PAH1 domain have been examined by NMR: saturation transfer difference (STD) and heteronuclear single quantum coherence (HSQC) experiments. Together with docking calculations using Haddock, NMR chemical shift perturbations suggest the binding modes of a few compounds to the PAH1 domain. NMR reveals that the binding compounds have some rotational isomers in their unbound states; however, Haddock shows that a few rotational isomers adopt fully the mSin3 binding pocket. Thus, NMR will be a key player to develop efficient compounds to recover from the severe neurological diseases.

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Authors and Affiliations

  1. Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan

    Jun-ichi Kurita, Yuuka Hirao & Yoshifumi Nishimura

  2. Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi, 467-8603, Japan

    Naoki Miyata

Authors
  1. Jun-ichi Kurita
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  2. Yuuka Hirao
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  3. Naoki Miyata
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  4. Yoshifumi Nishimura
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Correspondence to Yoshifumi Nishimura .

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Editors and Affiliations

  1. Royal Society of Chemistry, London, United Kingdom

    Graham A. Webb

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Kurita, Ji., Hirao, Y., Miyata, N., Nishimura, Y. (2018). NMR Screening of mSin3B Binding Compounds for the Interaction Inhibition with a Neural Repressor, NRSF/REST. In: Webb, G. (eds) Modern Magnetic Resonance. Springer, Cham. https://doi.org/10.1007/978-3-319-28388-3_64

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