ANTICOAGULANT PROTEIN COMPLEX STRUCTURE AND FUNCTION
抗凝蛋白复合物的结构和功能
基本信息
- 批准号:6638726
- 负责人:
- 金额:$ 24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-02-05 至 2005-07-31
- 项目状态:已结题
- 来源:
- 关键词:X ray crystallography activation product active sites anticoagulants cellular pathology coagulation factor VIII cofactor conformation enzyme activity enzyme structure enzyme substrate complex molecular pathology protein C protein binding protein structure function proteolysis thrombin thrombomodulin venous thrombosis zymogens
项目摘要
DESCRIPTION (Applicant's Description Verbatim): The enzymatic phase of the
anticoagulation system functions by the proteolytic digestion and
down-regulation of the procoagulant cofactors factors VIIla and Va by the
enzyme activated protain C(APC). Hereditary defects in this system lead to a
congenital predisposition to venous thrombosis. The pathway is initiated when
thrombin (T) binds to thrombomodulin (TM) on the endothelium and undergoes a
cofactor dependent allosteric conformational change. In the TM bound
conformation, thrombin loses its procoagulant activity, and gains an
alternative substrate selectivity. The T-TM complex now recognizes the zymogen
protein C as its substrate and very efficiently activates it. Thus, the major
procoagulant enzyme takes on an anticoagulant activity and catalyzes its own
down-regulation as a result of this cofactor induced allosteric modulation. The
structural nature of this transition is completely unknown.
If we could understand this specificity switch on a structural basis, we might
begin to design therapeutic agents which could bind to thrombin and shift it
from a procoagulant towards an anticoagulant activity. Based on the results of
APC infusion in septic shock, this therapeutic approach leads to a wider window
of efficacy without increased bleeding. We propose to study the structure and
function of the T-TM complex with X-ray crystallography to understand the
structural origin of thrombin's anticoagulant activity. We have grown
diffracting crystals of one form of this complex and are currently solving its
structure. We plan to build on this initial success to solve the structures of
related complexes, each designed to show an additional aspect of this activity,
and to apply our findings towards explaining the ability of some small
molecules and thrombin point mutations to achieve partial anti-coagulant
activity. Ultimately we will undertake structure based drug design to improve
these partial effects.
描述(申请人的逐字描述):酶的酶相
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)
A three-dimensional homology model of the O-acetylserine sulfhydrylase-B from Salmonella typhimurium.
鼠伤寒沙门氏菌 O-乙酰丝氨酸硫化氢解酶-B 的三维同源模型。
- DOI:10.2174/092986606774502126
- 发表时间:2006
- 期刊:
- 影响因子:1.6
- 作者:Rabeh,WaelM;Mather,Timothy;Cook,PaulF
- 通讯作者:Cook,PaulF
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{{ truncateString('TIMOTHY A. MATHER', 18)}}的其他基金
ANTICOAGULANT PROTEIN COMPLEX STRUCTURE AND FUNCTION
抗凝蛋白复合物的结构和功能
- 批准号:
6537936 - 财政年份:2001
- 资助金额:
$ 24万 - 项目类别:
ANTICOAGULANT PROTEIN COMPLEX STRUCTURE AND FUNCTION
抗凝蛋白复合物的结构和功能
- 批准号:
6232546 - 财政年份:2001
- 资助金额:
$ 24万 - 项目类别:














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