Structural basis for recognition of SV2 by type E botulinum neurotoxin

E型肉毒杆菌神经毒素识别SV2的结构基础

基本信息

  • 批准号:
    10281936
  • 负责人:
  • 金额:
    $ 23.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-07-09 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

Abstract Botulinum neurotoxins (BoNTs) are produced by the bacterium Clostridium botulinum, which are the causative agents of neuroparalytic disease botulism. Nevertheless, type A and type B botulinum neurotoxins (BoNT/A and BoNT/B) have been successfully used in clinic for a variety of aesthetic and therapeutic applications. The high potency of BoNTs relies on the specific and efficient binding and uptake of BoNTs by motor neurons at neuromuscular junctions. Inside the neurons, BoNTs cleave SNARE complex and block the release of acetylcholine, resulting in paralysis of the affected muscles. It is well accepted that most BoNTs synergistically bind specific protein receptors and gangliosides on motor neurons for cell entry. Remarkably, BoNTs develop diverse binding modes for protein receptor recognition, in contrast to a conserved ganglioside-binding mode. In this study, we will focus on the type E toxin (BoNT/E) that is the least studied human pathogenic BoNT in comparison to well-characterized BoNT/A and BoNT/B. Paradoxically, BoNT/E is currently in clinic trial as a new therapeutic and aesthetic product, which displays distinct pharmacological and clinic features when compared to BoNT/A and BoNT/B. At the molecular level, BoNT/E recognizes two of the three isoforms of synaptic vesicle glycoprotein 2 (SV2A and SV2B) as its neuronal receptors for cell entry, but not the closely related SV2C isoform. As SV2A, 2B, and 2C have different tissue distribution in vivo, a better understanding of how BoNT/E recognizes SV2A, 2B, and 2C differentially is crucial to understand the therapeutic profiles of BoNT/E-based drugs as well as to develop new indications. To this end, we propose two Specific Aims using an integrated approach that combines X-ray crystallography, site-directed mutagenesis, and binding assays. In Aim 1, we propose to study the structural basis for recognition of SV2A by BoNT/E. In Aim 2, we aim to understand the affinity and specificity requirements for BoNT/E to recognize three SV2 isoforms, while all the structural findings will be verified by structure-based mutagenesis studies. The achievement of our goals will help to understand the unique pharmacological and clinical profiles of BoNT/E, as well as to facilitate the design of new countermeasures against BoNT/E.
摘要

项目成果

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Rongsheng Jin其他文献

Rongsheng Jin的其他文献

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{{ truncateString('Rongsheng Jin', 18)}}的其他基金

A versatile structure-based therapeutic platform for development of VHH-based antitoxin and antiviral agents
一个多功能的基于结构的治疗平台,用于开发基于 VHH 的抗毒素和抗病毒药物
  • 批准号:
    10560883
  • 财政年份:
    2023
  • 资助金额:
    $ 23.55万
  • 项目类别:
Developing broad-spectrum therapeutics against C. difficile toxins
开发针对艰难梭菌毒素的广谱疗法
  • 批准号:
    10181652
  • 财政年份:
    2021
  • 资助金额:
    $ 23.55万
  • 项目类别:
Structural basis for recognition of SV2 by type E botulinum neurotoxin
E型肉毒杆菌神经毒素识别SV2的结构基础
  • 批准号:
    10448471
  • 财政年份:
    2021
  • 资助金额:
    $ 23.55万
  • 项目类别:
Developing broad-spectrum therapeutics against C. difficile toxins
开发针对艰难梭菌毒素的广谱疗法
  • 批准号:
    10548826
  • 财政年份:
    2021
  • 资助金额:
    $ 23.55万
  • 项目类别:
Developing broad-spectrum therapeutics against C. difficile toxins
开发针对艰难梭菌毒素的广谱疗法
  • 批准号:
    10348784
  • 财政年份:
    2021
  • 资助金额:
    $ 23.55万
  • 项目类别:
Structural basis of Rho glucosylation by Clostridium difficile toxins
艰难梭菌毒素 Rho 糖基化的结构基础
  • 批准号:
    10308686
  • 财政年份:
    2020
  • 资助金额:
    $ 23.55万
  • 项目类别:
Molecular mechanisms of botulinum neurotoxin neutralization
肉毒杆菌神经毒素中和的分子机制
  • 批准号:
    9160875
  • 财政年份:
    2016
  • 资助金额:
    $ 23.55万
  • 项目类别:
Molecular mechanisms of botulinum neurotoxin neutralization
肉毒杆菌神经毒素中和的分子机制
  • 批准号:
    9918242
  • 财政年份:
    2016
  • 资助金额:
    $ 23.55万
  • 项目类别:
Molecular mechanisms of botulinum neurotoxin neutralization
肉毒杆菌神经毒素中和的分子机制
  • 批准号:
    9271846
  • 财政年份:
    2016
  • 资助金额:
    $ 23.55万
  • 项目类别:
Structural mechanism for recognition of host receptor by botulinum neurotoxin A
A型肉毒杆菌神经毒素识别宿主受体的结构机制
  • 批准号:
    9238660
  • 财政年份:
    2016
  • 资助金额:
    $ 23.55万
  • 项目类别:

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