Molecular Basis of Blood Coagulation Regulation
凝血调节的分子基础
基本信息
- 批准号:7819176
- 负责人:
- 金额:$ 0.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-06-08 至 2009-10-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAmino AcidsAngiogenesis InhibitorsAnticoagulantsAntithrombin IIIAntithrombinsAutolysisBindingBinding SitesBlood ClotBlood ProteinsBlood coagulationBurialCleaved cellCoagulation ProcessComplexDockingElementsEndothelial CellsEngineeringEpitopesEventFactor IXaFactor XaFamilyGenerationsGlycosaminoglycansGoalsHeatingHemostatic functionHeparan Sulfate ProteoglycanHeparinHeparin BindingHeparitin SulfateInorganic SulfatesLengthLinkMalignant NeoplasmsMapsMediatingMolecularMolecular ConformationPeptide HydrolasesPhysiologicalProtease InhibitorProteolysisReactionRegulationRoleS cerevisiae SWI3 proteinSeriesSerpinsSignal TransductionSiteSpecificityStructureTestingUnspecified or Sulfate Ion SulfatesVertebratesantitumor drugbasebeta pleated sheetcardiovascular disorder preventiondesignimprovedmimeticsnovelreceptor
项目摘要
The serpin family coagulation protease inhibitor, antithrombin and its glycosaminoglycan activators, heparin
and heparan sulfate, comprise a key anticoagulant mechanism which is essential for maintaining hemostasis
in vertebrates. Intriguingly, antithrombin has been recently shown to possess antiangiogenic and antitumor
functions whose physiologic role remains to be determined. To advance our long-term goal of elucidating the
molecular mechanisms by which antithrombin carries out its physiologically relevant functions, we propose to
pursue three specific aims: 1) We have previously shown that the molecular determinants which mediate the
specificity of heparin-activated antithrombin for blood clotting proteases reside both in an exposed reactive
center loop of the serpin and in exosite regions outside the loop. We propose to map these exosite regions
on antithrombin and on factor Xa and factor IXa and determine the mechanism by which the exosites
mediate heparin rate enhancement of antithrombin reactions with the proteases; 2) Antithrombin circulates in
an unusual low-activity conformation in which the reactive loop is partially buried in beta-sheet A, but is
induced by heparin into a high-activity conformation resembling that of other serpins in which the reactive
loop is expelled from the sheet. We propose to identify the molecular determinants of this reactive loop
conformational switch and delineate the sequence of molecular events in the heparin binding site which
trigger the conformational switch; 3) Antithrombin expresses a potent antiangiogenic activity when it
undergoes conformational changes which occur spontaneously or are induced by cleavage in the reactive
loop and which result in the burial of the reactive loop into beta-sheet A. We will determine the structural
basis for the antiangiogenic activity of cleaved, latent and a novel prelatent form of antithrombin. The role of
specific endothelial cell binding sites in this activity and whether these binding sites involve a protein receptor
and/or specific domains of a heparan sulfate proteoglycan will be determined. The proposed studies are
expected to provide increased understanding at the molecular level of the function of a key natural
anticoagulant and antiangiogenic blood protein. This understanding is expected to facilitate the rational
design of a new generation of anticoagulant and antitumor drugs for the treatment and prevention of
cardiovascular diseases and cancer.
Serpin家族凝血蛋白酶抑制剂,抗凝血酶及其糖胺聚糖激活剂肝素
硫酸乙酰肝素,包括一个关键的抗凝机制,对于维持止血至关重要
在脊椎动物中。有趣的是,抗凝血酶最近已证明具有抗血管生成和抗肿瘤
生理作用的功能尚待确定。促进我们阐明的长期目标
抗凝血酶执行其生理相关功能的分子机制,我们建议
追求三个特定目的:1)我们先前已经表明,介导的分子决定因素
肝素激活的抗凝血酶对血液凝结蛋白酶的特异性都存在于暴露的反应性中
塞普蛋白的中心环和循环外的外部区域。我们建议映射这些外部区域
在抗凝血酶和因子Xa和因子IXA上,并确定外粒子的机制
介导与蛋白酶抗凝血酶反应的肝素速率提高; 2)抗凝血酶在
一个不寻常的低活动性构象,其中反应循环被部分埋在beta表A中,但是
由肝素诱导的高活动性构象,类似于其他丝丁的构象,其中反应性
循环被从床单上驱逐出去。我们建议确定该反应循环的分子决定因素
构象开关并描述肝素结合位点中分子事件的序列
触发构象开关; 3)抗凝血酶在其时表达有效的抗血管生成活性
经历自发发生的构象变化,或者是通过反应性裂解引起的
循环和导致反应循环埋入beta表A。我们将确定结构性
裂解,潜在和新型抗凝血酶的抗血管生成活性的基础。的作用
该活性中的特定内皮细胞结合位点以及这些结合位点是否涉及蛋白质受体
和/或乙par硫酸盐蛋白聚糖的特定结构域将被确定。拟议的研究是
预计将在关键自然的功能的分子水平上增加理解
抗凝剂和抗血管生成血蛋白。这种理解有望促进理性
新一代抗凝剂和抗肿瘤药物的设计,用于治疗和预防
心血管疾病和癌症。
项目成果
期刊论文数量(76)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Importance of tryptophan 49 of antithrombin in heparin binding and conformational activation.
抗凝血酶色氨酸 49 在肝素结合和构象激活中的重要性。
- DOI:10.1021/bi050741i
- 发表时间:2005
- 期刊:
- 影响因子:2.9
- 作者:Monien,BernhardH;Krishnasamy,Chandravel;Olson,StevenT;Desai,UmeshR
- 通讯作者:Desai,UmeshR
Antiangiogenic forms of antithrombin specifically bind to the anticoagulant heparin sequence.
- DOI:10.1021/bi801656u
- 发表时间:2008-12-23
- 期刊:
- 影响因子:2.9
- 作者:Schedin-Weiss S;Richard B;Hjelm R;Olson ST
- 通讯作者:Olson ST
Decreased affinity of recombinant antithrombin for heparin due to increased glycosylation.
由于糖基化增加,重组抗凝血酶与肝素的亲和力降低。
- DOI:10.1042/bj2860793
- 发表时间:1992
- 期刊:
- 影响因子:0
- 作者:Björk,I;Ylinenjärvi,K;Olson,ST;Hermentin,P;Conradt,HS;Zettlmeissl,G
- 通讯作者:Zettlmeissl,G
Immunologic evidence for insertion of the reactive-bond loop of antithrombin into the A beta-sheet of the inhibitor during trapping of target proteinases.
在捕获目标蛋白酶期间,抗凝血酶的反应键环插入抑制剂的 Aβ-片层的免疫学证据。
- DOI:10.1021/bi00077a002
- 发表时间:1993
- 期刊:
- 影响因子:2.9
- 作者:Björk,I;Nordling,K;Olson,ST
- 通讯作者:Olson,ST
Replacement of Phe274 with conserved residue Tyr274 for reactive center loop expulsion in antithrombin.
- DOI:10.1177/1076029609360529
- 发表时间:2011-06
- 期刊:
- 影响因子:0
- 作者:Duhan U
- 通讯作者:Duhan U
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Steven T. Olson其他文献
Steven T. Olson的其他文献
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{{ truncateString('Steven T. Olson', 18)}}的其他基金
Structural Basis of Serpin Function and Regulation
Serpin 功能和调节的结构基础
- 批准号:
7819189 - 财政年份:2009
- 资助金额:
$ 0.72万 - 项目类别:
Structural Basis of Serpin Function and Regulation
Serpin 功能和调节的结构基础
- 批准号:
7166101 - 财政年份:2004
- 资助金额:
$ 0.72万 - 项目类别:
Structural Basis of Serpin Function and Regulation
Serpin 功能和调节的结构基础
- 批准号:
6999372 - 财政年份:2004
- 资助金额:
$ 0.72万 - 项目类别:
Structural Basis of Serpin Function and Regulation
Serpin 功能和调节的结构基础
- 批准号:
6852375 - 财政年份:2004
- 资助金额:
$ 0.72万 - 项目类别:
Structural Basis of Serpin Function and Regulation
Serpin 功能和调节的结构基础
- 批准号:
7329181 - 财政年份:2004
- 资助金额:
$ 0.72万 - 项目类别:
Structural Basis of Serpin Function and Regulation
Serpin 功能和调节的结构基础
- 批准号:
7535011 - 财政年份:2004
- 资助金额:
$ 0.72万 - 项目类别:
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