...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Phenothiazines inhibit S100A4 function by inducing protein oligomerization
【24h】

Phenothiazines inhibit S100A4 function by inducing protein oligomerization

机译：吩噻嗪通过诱导蛋白质低聚来抑制S100A4功能

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

S100A4, a member of the S100 family of Ca~(2+)-binding proteins, regulates carcinoma cell motility via interactions with myosin-IIA. Numerous studies indicate that S100A4 is not simply a marker for metastatic disease, but rather has a direct role in metastatic progression. These observations suggest that S100A4 is an excellent target for therapeutic intervention. Using a unique biosensor-based assay, trifluoperazine (TFP) was identified as an inhibitor that disrupts the S100A4/myosin-IIA interaction. To examine the interaction of S100A4 with TFP, we determined the 2.3 A crystal structure of human Ca~(2+)-S100A4 bound to TFP. Two TFP molecules bind within the hydrophobic target binding pocket of Ca~(2+) -S100A4 with no significant conformational changes observed in the protein upon complex formation. NMR chemical shift perturbations are consistent with the crystal structure and demonstrate that TFP binds to the target binding cleft of S100A4 in solution. Remarkably, TFP binding results in the assembly of five Ca~(2+)-S100A4/TFP dimers into a tightly packed pentameric ring. Within each pentamer most of the contacts between S100A4 dimers occurs through the TFP moieties. The Ca~(2+)-S100A4/prochlorperazine (PCP) complex exhibits a similar pentameric assembly. Equilibrium sedimentation and cross-linking studies demonstrate the cooperative formation of a similarly sized S100A4/TFP oligomer in solution. Assays examining the ability of TFP to block S100A4-mediated disassembly of myosin-IIA filaments demonstrate that significant inhibition of S100A4 function occurs only at TFP concentrations that promote S100A4 oligomerization. Together these studies support a unique mode of inhibition in which phenothiazines disrupt the S100A4/ myosin-IIA interaction by sequestering S100A4 via small molecule-induced oligomerization.
机译：S100A4是Ca〜（2+）结合蛋白S100家族的成员，它通过与肌球蛋白IIA的相互作用来调节癌细胞的运动性。大量研究表明，S100A4不仅是转移性疾病的标志物，而且在转移进程中具有直接作用。这些观察结果表明，S100A4是治疗干预的理想靶标。使用独特的基于生物传感器的测定法，三氟拉嗪（TFP）被鉴定为破坏S100A4 /肌球蛋白-IIA相互作用的抑制剂。为了检查S100A4与TFP的相互作用，我们确定了人Ca〜（2 +）-S100A4与TFP结合的2.3 A晶体结构。两个TFP分子在Ca〜（2+）-S100A4的疏水目标结合口袋中结合，在复合物形成后在蛋白质中未观察到明显的构象变化。 NMR化学位移扰动与晶体结构一致，并证明TFP结合到溶液中S100A4的目标结合缝上。值得注意的是，TFP结合导致五个Ca〜（2 +）-S100A4 / TFP二聚体组装成紧密堆积的五聚环。在每个五聚体中，S100A4二聚体之间的大多数接触通过TFP部分发生。 Ca〜（2 +）-S100A4 /氯丙嗪（PCP）配合物表现出相似的五聚体组装。平衡沉降和交联研究证明了溶液中大小相似的S100A4 / TFP低聚物的协同形成。检验TFP阻断S100A4介导的肌球蛋白IIA细丝分解的能力的试验表明，只有在促进S100A4寡聚的TFP浓度下，S100A4功能才会受到明显抑制。这些研究共同支持一种独特的抑制方式，其中吩噻嗪通过通过小分子诱导的低聚作用隔离S100A4，从而破坏S100A4 /肌球蛋白与IIA的相互作用。

著录项

  • 来源
  • 作者

    Vladimir N. Malashkevich; Natalya G. Dulyaninova; Udupi A. Ramagopal; Melissa A. Liriano; Kristen M. Varney; David Knight; Michael Brenowitz; David J. Weber; Steven C. Almo; Anne R. Bresnick;

  • 作者单位

    Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461;

    Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461;

    Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461;

    Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 North Greene Street, Baltimore, MD, 21201;

    Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 North Greene Street, Baltimore, MD, 21201;

    Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY United Kingdom;

    Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461;

    Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 North Greene Street, Baltimore, MD, 21201;

    Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461;

    Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 North Greene Street, Baltimore, MD, 21201;

  • 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

    calcium; X-ray crystallography; NMR; small molecule inhibitor; metastasis;

    机译：钙;X射线晶体学;NMR;小分子抑制剂转移;

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号