...
  • 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 >An amantadine-sensitive chimeric BM2 ion channel of influenza B virus has implications for the mechanism of drug inhibition
【24h】

An amantadine-sensitive chimeric BM2 ion channel of influenza B virus has implications for the mechanism of drug inhibition

机译：乙型流感病毒对金刚烷胺敏感的嵌合BM2离子通道对药物抑制机制有影响

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

Influenza A virus M2 (A/M2) and the influenza B virus BM2 are both small integral membrane proteins that form proton-selective ion channels. Influenza A virus A/M2 channel is the target of the antiviral drug amantadine (and its methyl derivative rimantadine), whereas BM2 channel activity is not affected by the drug. The atomic structure of the pore-transmembrane (TM) domain peptide has been determined by x-ray crystallography [Stouffer et al. (2008) Nature 451:596-599] and of a larger M2 peptide by NMR methods [Schnell and Chou (2008) Nature 451:591-595]. The crys-tallographic data show electron density (at 3.5 A resolution) in the channel pore, consistent with amantadine blocking the pore of the channel. In contrast, the NMR data show 4 rimantadine molecules bound on the outside of the helices toward the cytoplasmic side of the membrane. Drug binding includes interactions with residues 40-45 and a polar hydrogen bond between rimantadine and aspartic acid residue 44 (D44). These 2 distinct drug-binding sites led to 2 incompatible drug inhibition mechanisms. We have generated chimeric channels between amantadine-sensitive A/M2 and amantadine-insensitive BM2 designed to define the drug-binding site. Two chimeras containing 5 residues of the A/M2 ectodomain and residues 24-36 of the A/M2 TM domain show 85% amanta-dine/rimantadine sensitivity and specific activity comparable to that of WT BM2. These functional data suggest that the amanta-dine/rimantadine binding site identified on the outside of the 4 helices is not the primary site associated with the pharmacologic inhibition of the A/M2 ion channel.
机译：甲型流感病毒M2（A / M2）和乙型流感病毒BM2都是形成质子选择性离子通道的小整体膜蛋白。 A型流感病毒A / M2通道是抗病毒药物金刚烷胺（及其甲基衍生物金刚乙胺）的靶标，而BM2通道活性不受该药物的影响。孔跨膜（TM）结构域肽的原子结构已经通过X射线晶体学测定[Stouffer等人。 （2008）Nature 451：596-599]和更大的M2肽通过NMR方法[Schnell and Chou（2008）Nature 451：591-595]。晶体结晶学数据显示通道孔中的电子密度（分辨率为3.5 A），与金刚烷胺阻断通道孔一致。相比之下，NMR数据显示在螺旋的外侧朝着膜的细胞质一侧结合了4个金刚烷胺分子。药物结合包括与残基40-45和金刚乙胺与天冬氨酸残基44（D44）之间的极性氢键相互作用。这两个不同的药物结合位点导致2个不兼容的药物抑制机制。我们已经在金刚烷胺敏感的A / M2和金刚烷胺不敏感的BM2之间生成了嵌合通道，用于定义药物结合位点。包含5个A / M2胞外域残基和A / M2 TM域的残基24-36的两个嵌合体显示出85％的金刚烷胺/金刚烷胺敏感性和比活性与WT BM2相当。这些功能数据表明，在4个螺旋的外侧确定的金刚烷胺/金刚烷胺结合位点不是与A / M2离子通道的药理抑制作用相关的主要位点。

著录项

  • 来源
  • 作者

    Yuki Ohigashi; Chunlong Ma; Xianghong Jing; Victoria Balannick; Lawrence H. Pinto; Robert A. Lamb;

  • 作者单位

    Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208-3500;

    Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208-3500;

    Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, IL 60208-3500;

    Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208-3500;

    Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208-3500;

    Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, IL 60208-3500 Howard Hughes Medical Institute, Northwestern University, Evanston, IL 60208-3500;

  • 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

    inhibition; binding site; proton-selective;

    机译：抑制;结合位点;质子选择性;

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