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首页> 外文期刊>Biochemistry >Structural Analysis of Botulinum Neurotoxin Serotype F Light Chain:Implications on Substrate Binding and Inhibitor Design
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Structural Analysis of Botulinum Neurotoxin Serotype F Light Chain:Implications on Substrate Binding and Inhibitor Design

机译：肉毒杆菌神经毒素血清型F轻链的结构分析：对底物结合和抑制剂设计的影响

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摘要

The seven serologically distinct Clostridium botulinum neurotoxins (BoNTs A-G) are zinc endopeptidases which block the neurotransmitter release by cleaving one of the three proteins of the soluble N-ethylmaleimide-sensitive-factor attachment protein receptor complex (SNARE complex) essential for the fusion of vesicles containing neurotransmitters with target membranes.These metallopeptidases exhibit unique specificity for the substrates and peptide bonds they cleave.Development of countermeasures and therapeutics for BoNTs is a priority because of their extreme toxicity and potential misuse as biowarfare agents.Though they share sequence homology and structural similarity,the structural information on each one of them is required to understand the mechanism of action of all of them because of their specificity.Unraveling the mechanism will help in the ultimate goal of developing inhibitors as antibotulinum drugs for the toxins.Here,we report the high-resolution structure of active BoNT/F catalytic domain in two crystal forms.The structure was exploited for modeling the substrate binding and identifying the S1 subsite and the putative exosites which are different from BoNT/A or BoNT/B.The orientation of docking of the substrate at the active site is consistent with the experimental BoNT/A-LC:SNAP-25 peptide model and our proposed model for BoNT/E-LC:SNAP-25.
机译：七种血晶不同的梭菌肉毒杆菌（Bonts Ag）是锌内肽酶，其通过切割可溶性的N-乙基马来酰亚胺敏感因子附着蛋白受体复合物（Snare Complex）的三种蛋白质中的一种来阻断神经递质释放酶，所述囊泡是必不可少的囊泡的融合含有靶膜的神经递质。这些金属肽酶对底物和肽键具有独特的特异性，它们的粘合剂和肽键合出。由于它们的极端毒性和潜在滥用作为BioWarfare代理，因此对对策和治疗性的抗衡度和治疗性是优先级。虽然它们共享序列同源性和结构相似性，他们中的每一个的结构信息是由于他们的特异性而了解所有这些的机制。如果他们的特异性，这种机制将有助于在毒素中发育抑制剂的最终目标。我们报告高分辨率的主动骚乱结构/ F催化结构域以两种晶体形式。利用结构用于对基板结合和识别S1底座的结构和鉴定与Bont / A或Bont / B不同的推定的内脏。基板在活性位点对接的取向与实验性BONT / A-LC：Snap-25肽模型以及我们的Bont / E-LC：SNAP-25的建议模型一致。

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  • 来源
    《Biochemistry》 |2005年第35期|共8页
  • 作者

    Rakhi Agarwal; Thomas Binz; Subramanyam Swaminathan;

  • 作者单位

    Biology Department Brookhaven National Laboratory Upton New York 11973 and Department of Biochemistry Medizinische Hochschule Hannover 30623 Hannover Germany;

    Biology Department Brookhaven National Laboratory Upton New York 11973 and Department of Biochemistry Medizinische Hochschule Hannover 30623 Hannover Germany;

    Biology Department Brookhaven National Laboratory Upton New York 11973 and Department of Biochemistry Medizinische Hochschule Hannover 30623 Hannover Germany;

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  • 正文语种 eng
  • 中图分类 生物化学;
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