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
- 来源:
- 关键词:AcetylcholineAchievementAffectAffinityAlpacaAmino Acid SubstitutionAntibodiesBacteriaBacterial ToxinsBindingBinding SitesBiologicalBiological AssayBontoxilysinBotoxBotulismCell Surface ReceptorsCell surfaceCellsChimeric ProteinsChinaCleaved cellClinicClinicalClostridium botulinumComplexCosmeticsCrystallizationCustomDataDiseaseDrug or chemical Tissue DistributionEstheticsGTP-Binding Protein alpha Subunits, GsGangliosidesGlycoproteinsGoalsHumanKnowledgeKoreaLinkMediatingMedicineModelingMolecularMotor NeuronsMuscleMutagenesisNeuromuscular JunctionNeuronsParalysedPathogenicityPeptidesPharmaceutical PreparationsPharmacologyPolysaccharidesProcessPropertyProtein IsoformsProteinsReceptor CellResolutionSNAP receptorSeriesSerotypingSite-Directed MutagenesisSpecificityStructureSynaptic VesiclesSyndromeTherapeuticToxic effectToxinX-Ray Crystallographyanthrax lethal factorbasebotulinum toxin type Bbotulinum toxin type Eclinical applicationclinical developmentdesignganglioside receptorimprovedin vivoinnovationnanobodiesnovelnovel therapeuticsprotein complexpublic health relevancereceptorreceptor bindinguptake
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
肉毒杆菌神经毒素(BoNT)由细菌肉毒梭菌(Clostridium Botulinum)产生,其是肉毒杆菌毒素的致病因子。
神经麻痹性疾病肉毒杆菌中毒的病原体。然而,A型和B型肉毒杆菌神经毒素(BoNT/A和
BoNT/B)已经成功地用于临床上的各种美容和治疗应用。高
BoNTs的效力依赖于运动神经元特异性和有效地结合和摄取BoNTs,
神经肌肉接头在神经元内,BoNTs切割SNARE复合物并阻断
乙酰胆碱,导致受影响的肌肉麻痹。人们普遍认为,大多数BONT协同
结合运动神经元上的特异性蛋白受体和神经节苷脂以进入细胞。值得注意的是,
与保守的神经节苷脂结合模式相反,蛋白质受体识别的多种结合模式。在
在这项研究中,我们将重点关注E型毒素(BoNT/E),这是研究最少的人类致病性BoNT,
与充分表征的BoNT/A和BoNT/B进行比较。巧合的是,BoNT/E目前正作为一种新的
治疗和美容产品,显示出独特的药理和临床特点时,比较
到BoNT/A和BoNT/B。在分子水平上,BoNT/E识别突触囊泡的三种亚型中的两种
糖蛋白2(SV 2A和SV 2B)作为其神经元受体进入细胞,但不是密切相关的SV 2C亚型。
由于SV 2A、2B和2C在体内具有不同的组织分布,因此更好地理解BoNT/E如何识别
SV 2A、2B和2C的差异对于理解基于BoNT/E的药物的治疗特征也至关重要
开发新的适应症。为此,我们提出了两个具体目标,采用综合方法,
结合了X射线晶体学、定点诱变和结合分析。在目标1中,我们建议研究
BoNT/E识别SV 2A的结构基础。在目标2中,我们的目标是了解亲和力和特异性
BoNT/E识别三种SV 2亚型的要求,而所有结构发现将通过
基于结构的诱变研究。我们目标的实现将有助于理解
BoNT/E的药理学和临床概况,以及促进新对策的设计
针对BoNT/E。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Rongsheng Jin其他文献
Rongsheng Jin的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
- 批准号:
2335802 - 财政年份:2024
- 资助金额:
$ 23.55万 - 项目类别:
Standard Grant
Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
- 批准号:
2335801 - 财政年份:2024
- 资助金额:
$ 23.55万 - 项目类别:
Standard Grant
A Longitudinal Study of the Relationship between Participation in a Comprehensive Exercise Program and Academic Achievement
参加综合锻炼计划与学业成绩之间关系的纵向研究
- 批准号:
24K14615 - 财政年份:2024
- 资助金额:
$ 23.55万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Collaborative Research: Characterizing Best Practices of Instructors who Have Narrowed Performance Gaps in Undergraduate Student Achievement in Introductory STEM Courses
合作研究:缩小本科生 STEM 入门课程成绩差距的讲师的最佳实践
- 批准号:
2420369 - 财政年份:2024
- 资助金额:
$ 23.55万 - 项目类别:
Standard Grant
Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
- 批准号:
2335800 - 财政年份:2024
- 资助金额:
$ 23.55万 - 项目类别:
Standard Grant
WTG: Diffusion of Research on Supporting Mathematics Achievement for Youth with Disabilities through Twitter Translational Visual Abstracts
WTG:通过 Twitter 翻译视觉摘要传播支持残疾青少年数学成就的研究
- 批准号:
2244734 - 财政年份:2023
- 资助金额:
$ 23.55万 - 项目类别:
Standard Grant
The Impact of Emotional Experiences of Pride on Long-Term Goal Achievement Behaviors in Elite Athletes
骄傲的情感体验对优秀运动员长期目标实现行为的影响
- 批准号:
23K16740 - 财政年份:2023
- 资助金额:
$ 23.55万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Meta-Analysis of the Instructional-Relational Model of Student Engagement and Math Achievement: A Moderation and Mediation Approach
学生参与度和数学成绩的教学关系模型的元分析:一种调节和中介方法
- 批准号:
2300738 - 财政年份:2023
- 资助金额:
$ 23.55万 - 项目类别:
Standard Grant
Improving maths achievement in children with speech, language, and communication needs through 'collaborative vocabulary teaching'
通过“协作词汇教学”提高有言语、语言和交流需求的儿童的数学成绩
- 批准号:
2890475 - 财政年份:2023
- 资助金额:
$ 23.55万 - 项目类别:
Studentship
HSI Institutional Transformation Project: Retention and Achievement for Introductory STEM English Learners (RAISE)
HSI 机构转型项目:STEM 英语入门学习者的保留和成就 (RAISE)
- 批准号:
2225178 - 财政年份:2023
- 资助金额:
$ 23.55万 - 项目类别:
Continuing Grant














{{item.name}}会员




