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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Azidoblebbistatin, a photoreactive myosin inhibitor
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Azidoblebbistatin, a photoreactive myosin inhibitor

机译：Azidoblebbistatin，一种光反应性肌球蛋白抑制剂

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摘要

Photoreactive compounds are important tools in life sciences that allow precisely timed covalent crosslinking of ligands and targets. Using a unique technique we have synthesized azidoblebbistatin, which is a derivative of blebbistatin, the most widely used myosin inhibitor. Without UV irradiation azidoblebbistatin exhibits identical inhibitory properties to those of blebbistatin. Using UV irradiation, azidoblebbistatin can be covalently crosslinked to myosin, which greatly enhances its in vitro and in vivo effectiveness. Photo-cross-linking also eliminates limitations associated with the relatively low myosin affinity and water solubility of blebbistatin. The wavelength used for photo-crosslinking is not toxic for cells and tissues, which confers a great advantage in in vivo tests. Because the crosslink results in an irreversible association of the inhibitor to myosin and the irradiation eliminates the residual activity of unbound inhibitor molecules, azidobiebbistatin has a great potential to become a highly effective tool in both structural studies of actomyosin contractility and the investigation of cellular and physiological functions of myosin II. We used azidoblebbistatin to identify previously unknown low-affinity targets of the inhibitor (EC_(50) > 50 μM) in Dictyostelium discoideum, while the strongest interactant was found to be myosin II (EC_(50 )= 5 μM). Our results demonstrate that azidoblebbistatin, and potentially other azidated drugs, can become highly useful tools for the identification of strong- and weak-binding cellular targets and the determination of the apparent binding affinities in in vivo conditions.
机译：光反应性化合物是生命科学中的重要工具，可实现配体和靶标的精确定时共价交联。使用一种独特的技术，我们合成了叠氮抑菌素，它是最广泛使用的肌球蛋白抑制剂抑菌素的衍生物。没有紫外线照射，叠氮抑菌素显示出与抑菌素相同的抑制特性。使用紫外线照射，叠氮抑菌素可以与肌球蛋白共价交联，从而大大增强其体外和体内功效。光交联也消除了与抑肌素相对较低的肌球蛋白亲和力和水溶性有关的限制。用于光交联的波长对细胞和组织无毒，这在体内测试中具有很大的优势。由于交联导致抑制剂与肌球蛋白不可逆地缔合，并且辐射消除了未结合的抑制剂分子的残留活性，叠氮抑菌素有很大的潜力成为放线肌球蛋白收缩性结构研究以及细胞和生理学研究的高效工具肌球蛋白II的功能。我们使用叠氮抑菌素来鉴定盘基网柄菌中抑制剂的先前未知的低亲和力靶标（EC_（50）> 50μM），而发现最强的相互作用剂是肌球蛋白II（EC_（50）= 5μM）。我们的结果表明，叠氮抑菌素和可能的其他叠氮化药物可以成为高度有用的工具，用于鉴定强结合和弱结合的细胞靶标，并确定体内条件下的表观结合亲和力。

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  • 作者

    Miklos Kepiro; Boglarka H.Varkuti; Andrea Bodor; Gyorgy Hegyi; Laszlo Drahos; Mihaly Kovacs; Andras Malnasi-Csizmadia;

  • 作者单位

    Department of Biochemistry, Institute of Biology, Eotvos Lorand University, H-1117 Budapest, Hungary;

    Department of Biochemistry, Institute of Biology, Eotvos Lorand University, H-1117 Budapest, Hungary;

    Laboratory of Structural Chemistry and Biology, Institute of Chemistry, Eotvos Lorand University, H-1117 Budapest, Hungary;

    Department of Biochemistry, Institute of Biology, Eotvos Lorand University, H-1117 Budapest, Hungary,HAS-ELTE (Eotvos Lorand University-Hungarian Academy of Sciences) Molecular Biophysics Research Group, and Eotvos Lorand University, H-1117 Budapest, Hungary;

    lnstitute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1025 Budapest, Hungary;

    Department of Biochemistry, Institute of Biology, Eotvos Lorand University, H-1117 Budapest, Hungary,ELTE-MTA (Eotvos Lorand University-Hungarian Academy of Sciences)"Momentum" Motor Enzymology Research Group, Eotvos Lorand University, H-1117 Budapest, Hungary;

    Department of Biochemistry, Institute of Biology, Eotvos Lorand University, H-1117 Budapest, Hungary,HAS-ELTE (Eotvos Lorand University-Hungarian Academy of Sciences) Molecular Biophysics Research Group, and Eotvos Lorand University, H-1117 Budapest, Hungary;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    interactom profile; azidation; photoactivation;

    机译：互动档案叠氮化光活化;

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