• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A
【24h】

Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A

机译：肉毒杆菌神经毒素A识别突触小泡蛋白2C的结构基础

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

Botulinum neurotoxin A (BoNT/A) belongs to the most dangerous class of bio weapons. Despite this, BoNT/A is used to treat a wide range of common medical conditions such as migraines and a variety of ocular motility and movement disorders. BoNT/A is probably best known for its use as an antiwrinkle agent in cosmetic applications (including Botox and Dysport). BoNT/A application causes long-lasting flaccid paralysis of muscles through inhibiting the release of the neurotransmitter acetylcholine by cleaving synaptosomal-associated protein 25 (SNAP-25) within presynaptic nerve terminals. Two types of BoNT/A receptor have been identified, both of which are required for BoNT/A toxicity and are therefore likely to cooperate with each other: gangliosides and members of the synaptic vesicle glycoprotein 2 (SV2) family, which are putative transporter proteins that are predicted to have 12 transmembrane domains, associate with the receptor-binding domain of the toxin. Recently, fibroblast growth factor receptor 3 (FGFR3) has also been reported to be a potential BoNT/A receptor. In SV2 proteins, the BoNT/A-binding site has been mapped to the luminal domain, but the molecular details of the interaction between BoNT/A and SV2 are unknown. Here we determined the high-resolution crystal structure of the BoNT/A receptor-binding domain (BoNT/A-RBD) in complex with the SV2C luminal domain (SV2C-LD). SV2C-LD consists of a right-handed, quadrilateral p-helix that associates with BoNT/A-RBD mainly through backbone-to-backbone interactions at open β-strand edges, in a manner that resembles the inter-strand interactions in amyloid structures. Competition experiments identified a peptide that inhibits the formation of the complex. Our findings provide a strong platform for the development of novel antitoxin agents and for the rational design of BoNT/A variants with improved therapeutic properties.
机译：肉毒杆菌神经毒素A（BoNT / A）属于最危险的生物武器类别。尽管如此，BoNT / A仍可用于治疗各种常见的医学疾病，例如偏头痛，各种眼部运动和运动障碍。 BoNT / A可能以在化妆品中（包括肉毒杆菌毒素和Dysport）用作抗皱剂而闻名。 BoNT / A的应用通过在突触前神经末梢内裂解突触体相关蛋白25（SNAP-25），抑制神经递质乙酰胆碱的释放，从而导致肌肉持久性松弛性麻痹。已经鉴定出两种类型的BoNT / A受体，这两种都是BoNT / A毒性所必需的，因此可能相互协作：神经节苷脂和突触小泡糖蛋白2（SV2）家族的成员，它们是推定的转运蛋白。预计具有12个跨膜结构域，与毒素的受体结合结构域相关。最近，也已报道成纤维细胞生长因子受体3（FGFR3）是潜在的BoNT / A受体。在SV2蛋白中，BoNT / A结合位点已定位到腔结构域，但BoNT / A与SV2之间相互作用的分子细节未知。在这里，我们确定了BoNT / A受体结合结构域（BoNT / A-RBD）与SV2C腔结构域（SV2C-LD）的高分辨率晶体结构。 SV2C-LD由右旋的四边形p螺旋组成，该螺旋与BoNT / A-RBD主要通过开放的β链边缘处的主链间相互作用来结合，其方式类似于淀粉样蛋白结构中的链间相互作用。 。竞争实验确定了一种抑制复合物形成的肽。我们的发现为开发新型抗毒素剂和合理设计具有改良治疗特性的BoNT / A变体提供了强大的平台。

著录项

  • 来源
    《Nature》 |2014年第7481期|108-111|共4页
  • 作者

    Roger M. Benoit; Daniel Frey; Manuel Hilbert; Josta T. Kevenaar; Mara M. Wieser; Christian U. Stirnimann; David McMillan; Tom Ceska; Florence Lebon; Rolf Jaussi; Michel O.Steinmetz; Gebhard F. X. Schertler; Casper C. Hoogenraad; Guido Capitani; Richard A. Kammerer;

  • 作者单位

    Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland;

    Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland;

    Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland;

    Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands;

    Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland;

    Swiss Light Source, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland;

    UCB Celltech, UCB Pharma, UCB NewMedicines, Slough SL1 4EN, UK;

    UCB Celltech, UCB Pharma, UCB NewMedicines, Slough SL1 4EN, UK;

    UCB Pharma, UCB NewMedicines, B-1420 Braine-L'Alleud,Belgium;

    Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland;

    Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland;

    Department of Biology, ETH Zurich, CH-8093 Zurich, Switzerland;

    Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands;

    Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland;

    Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);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