...
  • 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 >Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX
【24h】

Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX

机译：肿瘤相关人碳酸酐酶IX催化域的晶体结构

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

Carbonic anhydrase (CA) IX is a plasma membrane-associated member of the α-CA enzyme family, which is involved in solid tumor acidification. It is a marker of tumor hypoxia and a prognostic factor in several human cancers. An aberrant increase in CA IX expression in chronic hypoxia and during development of various carcinomas contributes to tumorigenesis through at least two mechanisms: pH regulation and cell adhesion control. Here we report the X-ray structure of the catalytic domain of CA IX in complex with a classical, clinically used sulfonamide inhibitor, acetazolamide. The structure reveals a typical α-CA fold, which significantly differs from the other CA isozymes when the protein quaternary structure is considered. Thus, two catalytic domains of CA IX associate to form a dimer, which is stabilized by the formation of an intermolecular disulf ide bond. The active site clefts and the PG domains are located on one face of the dimer, while the C-termini are located on the opposite face to facilitate protein anchoring to the cell membrane. A correlation between the three-dimensional structure and the physiological role of the enzyme is here suggested, based on the measurement of the pH profile of the catalytic activity for the physiological reaction, CO_2 hydration to bicarbonate and protons. On the basis of the structural differences observed between CA IX and the other membrane-associated a-CAs, further prospects for the rational drug design of isozyme-specific CA inhibitors are proposed, given that inhibition of this enzyme shows antitumor activity both in vitro and in vivo.
机译：碳酸酐酶（CA）IX是与实体瘤酸化有关的α-CA酶家族的质膜相关成员。它是肿瘤缺氧的标志物，也是几种人类癌症的预后因素。在慢性缺氧和各种癌症发生过程中，CA IX表达异常增加，至少通过两种机制促进了肿瘤的发生：pH调节和细胞粘附控制。在这里，我们报告了CA IX催化域的X射线结构，该结构与经典的，临床上使用的磺酰胺抑制剂乙酰唑酰胺复合。该结构揭示了典型的α-CA折叠，当考虑蛋白质四级结构时，该折叠与其他CA同工酶显着不同。因此，CA IX的两个催化结构域缔合以形成二聚体，该二聚体通过形成分子间二硫键来稳定。活性位点的裂口和PG域位于二聚体的一个面上，而C末端位于相反的面上，以促进蛋白质锚定到细胞膜上。基于对生理反应，CO_2水合为碳酸氢根和质子的催化活性的pH曲线的测量，在此提出了酶的三维结构与酶的生理作用之间的相关性。根据CA IX与其他膜相关a-CA之间观察到的结构差异，提出同工酶特异性CA抑制剂合理药物设计的进一步前景，因为对该酶的抑制在体外和体外均显示出抗肿瘤活性。体内。

著录项

  • 来源
  • 作者

    Vincenzo Alterio; Mika Hilvo; Anna Di Fiore; Claudiu T. Supuran; Peiwen Pan; Seppo Parkkila; Andrea Scaloni; Jaromir Pastorek; Silvia Pastorekova; Carlo Pedone; Andrea Scozzafava; Simona Maria Monti; Giuseppina De Simone;

  • 作者单位

    Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Naples, Italy;

    Institute of Medical Technology and School of Medicine, University of Tampere and Tampere University Hospital, FI-33014 University of Tampere, Finland VTT Technical Research Centre of Finland, Tietotie 2, P.O. Box 1000, FI-02044 VTT, Espoo, Finland;

    Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Naples, Italy;

    Laboratorio di Chimica Bioinorganica, Universita degli Studi di Firenze, Polo Scientifico, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy;

    Institute of Medical Technology and School of Medicine, University of Tampere and Tampere University Hospital, FI-33014 University of Tampere, Finland;

    Institute of Medical Technology and School of Medicine, University of Tampere and Tampere University Hospital, FI-33014 University of Tampere, Finland;

    Proteomics and Mass Spectrometry Laboratory, ISPAAM-CNR, via Argine 1085, 80147 Naples, Italy;

    Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovak Republic;

    Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovak Republic;

    Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Naples, Italy;

    Laboratorio di Chimica Bioinorganica, Universita degli Studi di Firenze, Polo Scientifico, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy;

    Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Naples, Italy;

    Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Naples, Italy;

  • 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

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