Structural Diversity of Botulinum Toxin

肉毒杆菌毒素的结构多样性

• 批准号: 8260255
• 负责人: RAYMOND C STEVENS
• 金额: $ 54.07万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260255
• 关键词: Affect; Antibodies; Area; Binding; Biological; Bontoxilysin; Botulinum Toxins; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Clostridium botulinum; Collaborations; Complex; Databases; Development; Diagnostic; Dystonia; Emerging Communicable Diseases; Engineering; Family; Goals; Individual; Infectious Diseases Research; Intensive Care; Laboratories; Medical; Neuromuscular Diseases; Neurotoxins; Persons; Process; Production; Proteins; Receptor Cell; Research; Sampling; Serotyping; Structure; Therapeutic; Toxin; Variant; Work; biodefense; botulinum; chronic pain; disorder prevention; genetic analysis; genetic variant; improved; man; neutralizing antibody; next generation; novel; novel diagnostics; professor; progenitor; protein complex; receptor; receptor binding; structural biology; success; therapeutic development; three dimensional structure; tool; weapons

The botulinum neurotoxins, BoNTs, produced by Clostridium botulinum are among the most potent toxins known to man. The Centers for Disease Control and Prevention (CDC) has classified it as a potential bioweapon, Category A, because of its extreme potency and lethality, its ease of production and transport, and the need for prolonged intensive care among affected persons. This project participates on a collaboration focusing on the various serotypes and subtypes of the toxin with the overall goal of characterizing these variants at the DMA and protein level and developing a deeper understanding of neurotoxin action. We will focus on three major research areas: (1) continuing to deepen our understanding of the cell receptor recognition and binding processes as well as the translocation process by determining the structures of the toxin in complex with cell recognition receptor molecules, (2) developing a detailed understanding on how the recently developed antibodies (Abs), work and how we can then improve them, and (3) using structurebased approaches engineer the next generation broad spectrum diagnostic antibodies (working towards one antibody to recognize multiple toxin subtypes and serotypes). The study will characterize a number of BoNT variants to assess their impact on the development of diagnostics and therapeutics and to understand differences in biological action. In addition to the structures, the project will also produce highly purified protein samples that will be made available to its collaborators and other workers in the biodefense consortium.

由肉毒杆菌产生的肉毒杆菌神经毒素 BoNT 是最有效的毒素之一 为人类所知。美国疾病控制与预防中心 (CDC) 将其归类为潜在生物武器 A 类，因为它具有极高的效力和杀伤力，易于生产和运输，并且需要对受影响人员进行长期重症监护。该项目参与了一项专注于毒素的各种血清型和亚型的合作，总体目标是在 DMA 和蛋白质水平上表征这些变体，并加深对神经毒素作用的了解。我们将重点关注三个主要研究领域：（1）通过确定毒素与细胞识别受体分子复合物的结构，继续加深对细胞受体识别和结合过程以及易位过程的理解，（2）开发详细了解最近开发的抗体 (Ab) 的工作原理以及我们如何改进它们，以及 (3) 使用基于结构的方法设计下一代广谱诊断抗体（致力于一种抗体识别多种毒素亚型和血清型） 。该研究将表征许多 BoNT 变体，以评估它们对诊断和治疗开发的影响，并了解生物作用的差异。除了这些结构之外，该项目还将生产高度纯化的蛋白质样本，供其合作者和生物防御联盟的其他工作人员使用。