ANTICOAGULANT PROTEIN COMPLEX STRUCTURE AND FUNCTION

抗凝蛋白复合物的结构和功能

• 批准号: 6638726
• 负责人: TIMOTHY A. MATHER
• 金额: $ 24万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/6638726
• 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

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

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: Protein and peptide letters
• 影响因子: 1.6
• 作者: Rabeh,WaelM;Mather,Timothy;Cook,PaulF
• 通讯作者: Cook,PaulF