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(申请者逐字描述):酶促阶段
抗凝系统通过蛋白水解性消化和
促凝血辅因子Vi1a和Va的下调作用
酶激活蛋白C(APC)。这一系统中的遗传缺陷导致了
先天易患静脉血栓形成。该途径在以下情况下启动
凝血酶(T)与内皮上的血栓调节蛋白(TM)结合并经历
辅因子依赖的变构构象变化。在TM范围内
构象,凝血酶失去其促凝血活性,并获得
替代底物选择性。T-TM复合体现在识别酶原
蛋白C作为它的底物,非常有效地激活它。因此,少校
促凝血酶具有抗凝血活性,并催化自身
这种辅因子的下调导致变构调节。这个
这一过渡的结构性质完全未知。
如果我们能够在结构的基础上理解这种特定的转换,我们可能会
开始设计可以与凝血酶结合并转移它的治疗剂
从促凝剂转变为抗凝血剂。基于以下结果:
感染性休克的APC输注,这一治疗方法导致了更宽的窗口
在不增加出血的情况下提高疗效。我们建议研究它的结构和
用X射线结晶学研究T-TM复合体的功能
凝血酶抗凝血活性的结构来源。我们已经成长了
这种络合物的一种形式的衍射晶体,目前正在解决其
结构。我们计划在这一初步成功的基础上解决
相关的综合体,每个都旨在展示这一活动的另一个方面,
并应用我们的发现来解释一些小的
分子和凝血酶点突变实现部分抗凝
活动。最终,我们将进行基于结构的药物设计以改进
这些部分效应。
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: