A Novel Cholesterol-Dependent Cytolysin Receptor
一种新型胆固醇依赖性溶细胞素受体
基本信息
- 批准号:7324132
- 负责人:
- 金额:$ 30.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-01-15 至 2009-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffinityAlanineAntibodiesBacterial ToxinsBindingBinding SitesCellsChimera organismCholesterolCompetitive BindingComplementComplement Membrane Attack ComplexComplexCysteineCytolysinsDiseaseEventFamilyFlow CytometryFutureHumanImmunoprecipitationInvestigationLigandsLocationMapsMeasuresMembraneNumbersOrganismOryctolagus cuniculusPathogenesisPerceptionProteinsRoleSeriesSiteSpecies SpecificitySpecificityStagingStreptococcusStreptococcus intermediusStructureSulfhydryl CompoundsSurfaceSystemToxinbasedesigninhibitor/antagonistintermedilysinmembermembrane assemblymonomermutantnovelpathogenpathogenic bacteriaperforinreceptorreceptor bindingresearch study
项目摘要
DESCRIPTION (provided by applicant): The cholesterol-dependent cytolysins (CDCs) are a large family of related bacterial toxins produced by over 20 species of Gram-positive pathogenic bacteria. Several CDCs have been shown to contribute to the pathogenic mechanisms of these bacterial species. The CDCs are produced as soluble proteins that oligomerize into large pore-forming complexes on the surface of cholesterol-containing membranes. The presence of membrane cholesterol is required for the CDC pore-formation and is a hallmark of the CDCs. For over three decades the receptor for the CDCs was generally accepted as cholesterol but recent studies show that it is necessary for the prepore to pore conversion of the CDCs, an event that is downstream of membrane binding. Therefore, the longstanding dogma that the CDCs use cholesterol as their receptor appears less plausible. We have now determined that at least one member of the CDC family, intermedilysin (ILY) from Streptococcus intermedius, utilizes the GPI-anchored human CD59 (hCD59) as its receptor. Based on preliminary studies we hypothesize that 1) ILY domain 4 contains the residues required for binding to and specificity for hCD59, 2) the region and residues of hCD59 recognized by human complement proteins C8 and C9 also comprises the hCD59 binding site for ILY, and 3) ILY disengages from its receptor prior to pore formation. This proposal is designed to examine the interaction of ILY with hCD59 and to map out the structural domains of both ILY and hCD59 that are involved in this ligand-receptor interaction. The interaction of ILY with hCD59 will also be examined at various stages of the cytolytic mechanism to determine if the toxin disengages from receptor during the assembly of its pore complex. These hypotheses will be addressed in three specific aims that will establish the location of the binding sites on both hCD59 and ILY and will determine whether ILY undocks from receptor during the assembly of the pore-forming complex. The results of these studies will provide a basis for investigations of a new and significant aspect of the CDCs previously unavailable to the study of these toxins. The discovery and study of a CDC receptor will have a significant impact on the study of CDCs and will alter our perception of their role in a large number of diseases caused by a wide variety of Gram-positive pathogens.
描述(由申请人提供):胆固醇依赖性细胞素(CDC)是由20多种革兰氏阳性致病细菌产生的大型相关细菌毒素家族。已经显示出几种CDC有助于这些细菌物种的致病机制。 CDC作为可溶性蛋白产生,将含胆固醇膜表面的大型孔形成复合物成寡聚。 CDC孔形成需要膜胆固醇的存在,并且是CDC的标志。三十年来,CDC的受体普遍接受为胆固醇,但最近的研究表明,预货币需要进行孔洞的孔转换,CDC是膜结合的下游事件。因此,CDC使用胆固醇作为受体的长期教条似乎不太合理。现在,我们已经确定,来自Intermedius链球菌的CDC家族中至少有一个成员使用GPI锚定的人CD59(HCD59)作为其受体。基于初步研究,我们假设1)ILY结构域4包含与HCD59结合和特异性所需的残基,2)人类补体蛋白C8和C9所识别的HCD59的区域和残基还包括ILY的HCD59与其受体的结合位点,以及3)与其受体的结合。该提案旨在检查ILY与HCD59的相互作用,并绘制ILY和HCD59的结构域,这些结构域与这种配体相互作用相互作用涉及。还将在细胞溶解机制的各个阶段检查ILY与HCD59的相互作用,以确定其在其孔复合物组装过程中是否与受体脱离受体。这些假设将以三个特定的目的来解决,该目标将在HCD59和ILY上建立结合位点的位置,并确定在孔形成络合物组装过程中是否会从受体中解开ILY。这些研究的结果将为研究这些毒素研究以前无法使用的CDC的新和重要方面提供基础。对CDC受体的发现和研究将对CDC的研究产生重大影响,并将改变我们对它们在多种革兰氏阳性病原体引起的大量疾病中的作用的看法。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Crystallization and preliminary X-ray analysis of the human-specific toxin intermedilysin.
人类特异性毒素中间素的结晶和初步 X 射线分析。
- DOI:10.1107/s0907444903027240
- 发表时间:2004
- 期刊:
- 影响因子:0
- 作者:Polekhina,Galina;Giddings,KaraSue;Tweten,RodneyK;Parker,MichaelW
- 通讯作者:Parker,MichaelW
{{
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 }}
Rodney K. Tweten其他文献
Molecular cloning and expression of gene fragments from corynebacteriophage beta encoding enzymatically active peptides of diphtheria toxin
编码白喉毒素酶活性肽的β棒状噬菌体基因片段的分子克隆和表达
- DOI:
10.1128/jb.156.2.680-685.1983 - 发表时间:
1983 - 期刊:
- 影响因子:3.2
- 作者:
Rodney K. Tweten;Robert J Collier - 通讯作者:
Robert J Collier
Cloning and expression in Escherichia coli of the perfringolysin O (theta-toxin) gene from Clostridium perfringens and characterization of the gene product
产气荚膜梭菌产气荚膜溶血素 O(theta 毒素)基因在大肠杆菌中的克隆和表达以及基因产物的表征
- DOI:
10.1128/iai.56.12.3228-3234.1988 - 发表时间:
1988 - 期刊:
- 影响因子:3.1
- 作者:
Rodney K. Tweten - 通讯作者:
Rodney K. Tweten
Nucleotide sequence of the gene for perfringolysin O (theta-toxin) from Clostridium perfringens: significant homology with the genes for streptolysin O and pneumolysin
产气荚膜梭菌产气荚膜溶血素 O(theta 毒素)基因的核苷酸序列:与链球菌溶血素 O 和肺炎球菌溶血素基因显着同源
- DOI:
10.1128/iai.56.12.3235-3240.1988 - 发表时间:
1988 - 期刊:
- 影响因子:3.1
- 作者:
Rodney K. Tweten - 通讯作者:
Rodney K. Tweten
Rodney K. Tweten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('Rodney K. Tweten', 18)}}的其他基金
Pore Formation by Cholesterol Dependent Cytolysins
胆固醇依赖性溶细胞素形成孔
- 批准号:
10584602 - 财政年份:2021
- 资助金额:
$ 30.66万 - 项目类别:
Pore Formation by Cholesterol Dependent Cytolysins
胆固醇依赖性溶细胞素形成孔
- 批准号:
10348704 - 财政年份:2021
- 资助金额:
$ 30.66万 - 项目类别:
Pore Formation by Cholesterol Dependent Cytolysins
胆固醇依赖性溶细胞素形成孔
- 批准号:
10049602 - 财政年份:2021
- 资助金额:
$ 30.66万 - 项目类别:
A Novel Cholesterol-Dependent Cytolysin Receptor
一种新型胆固醇依赖性溶细胞素受体
- 批准号:
6860745 - 财政年份:2005
- 资助金额:
$ 30.66万 - 项目类别:
A Novel Cholesterol-Dependent Cytolysin Receptor
一种新型胆固醇依赖性溶细胞素受体
- 批准号:
7172320 - 财政年份:2005
- 资助金额:
$ 30.66万 - 项目类别:
A Novel Cholesterol-Dependent Cytolysin Receptor
一种新型胆固醇依赖性溶细胞素受体
- 批准号:
7007618 - 财政年份:2005
- 资助金额:
$ 30.66万 - 项目类别:
DOMAIN MAPPING CLOSTRIDIUM PERFRINGENS THETA TOXIN
产气荚膜梭菌 Theta 毒素的结构域图谱
- 批准号:
2004242 - 财政年份:1997
- 资助金额:
$ 30.66万 - 项目类别:
Pore Formation by Cholesterol Dependent Cytolysins
胆固醇依赖性溶细胞素形成孔
- 批准号:
8121859 - 财政年份:1997
- 资助金额:
$ 30.66万 - 项目类别:
DOMAIN MAPPING CLOSTRIDIUM PERFRINGENS THETA TOXIN
产气荚膜梭菌 Theta 毒素的结构域图谱
- 批准号:
2672473 - 财政年份:1997
- 资助金额:
$ 30.66万 - 项目类别:
DOMAIN MAPPING CLOSTRIDIUM PERFRINGENS THETA TOXIN
产气荚膜梭菌 Theta 毒素的结构域图谱
- 批准号:
6169992 - 财政年份:1997
- 资助金额:
$ 30.66万 - 项目类别:
相似国自然基金
基于计算生物学技术小分子农兽药残留物驼源单域抗体虚拟筛选与亲和力成熟 -以内蒙古阿拉善双峰驼为例
- 批准号:32360190
- 批准年份:2023
- 资助金额:34 万元
- 项目类别:地区科学基金项目
基于胞内蛋白亲和力标记策略进行新型抗类风湿性关节炎的选择性OGG1小分子抑制剂的发现
- 批准号:82304698
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
基于多尺度表征和跨模态语义匹配的药物-靶标结合亲和力预测方法研究
- 批准号:62302456
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
框架核酸多价人工抗体增强靶细胞亲和力用于耐药性肿瘤治疗
- 批准号:32301185
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
抗原非特异性B细胞进入生发中心并实现亲和力成熟的潜力与调控机制
- 批准号:32370941
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
相似海外基金
High-throughput thermodynamic and kinetic measurements for variant effects prediction in a major protein superfamily
用于预测主要蛋白质超家族变异效应的高通量热力学和动力学测量
- 批准号:
10752370 - 财政年份:2023
- 资助金额:
$ 30.66万 - 项目类别:
Biology and Molecular Biology of the Evolution of Macrophage-Tropic HIV-1
巨噬细胞趋向性 HIV-1 进化的生物学和分子生物学
- 批准号:
10882245 - 财政年份:2023
- 资助金额:
$ 30.66万 - 项目类别:
Uncovering the role of GPR75 as an activator of fatty acid transporters in non-alcoholic fatty liver disease (NAFLD)
揭示 GPR75 作为脂肪酸转运蛋白激活剂在非酒精性脂肪性肝病 (NAFLD) 中的作用
- 批准号:
10666762 - 财政年份:2023
- 资助金额:
$ 30.66万 - 项目类别:
Augmenting cancer checkpoint immunotherapies via microbially-derived metabolites
通过微生物衍生的代谢物增强癌症检查点免疫疗法
- 批准号:
10506732 - 财政年份:2023
- 资助金额:
$ 30.66万 - 项目类别:
Rational design and efficacy testing of vaccines against HCV
HCV疫苗的合理设计和功效测试
- 批准号:
10618256 - 财政年份:2022
- 资助金额:
$ 30.66万 - 项目类别: