STRUCTURE AND FUNCTION OF HEPARIN COFACTOR II
肝素辅因子 II 的结构和功能
基本信息
- 批准号:2415676
- 负责人:
- 金额:$ 41.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1996
- 资助国家:美国
- 起止时间:1996-05-01 至 2001-04-30
- 项目状态:已结题
- 来源:
- 关键词:X ray crystallography binding proteins carbohydrate structure chemical association chondroitin sulfate B cofactor embryonic stem cell enzyme activity enzyme inhibitors enzyme structure enzyme substrate complex genetically modified animals heparin human tissue immunocytochemistry laboratory mouse mucopolysaccharides mutant protein structure function synthetic peptide thrombin
项目摘要
DESCRIPTION: Six specific aims are identified. These include: 1)
investigating the mechanism by which heparin facilitates dissociation
between thrombin the HCII mutant Leu444 Arg; 2) to determine the
affects of synthetic reactive site peptides on the ability of heparin
cofactor 2 to serve as an inhibitor or substrate; 3) to identify
structures in dermatan sulfate required for high-affinity binding to
heparin cofactor II; 4) to crystallize heparin cofactor II and its
complexes with dermatan sulfate for x-ray analysis; 5) to
determine the location of endogenous heparin cofactor II in human and
murine tissues by immunohistochemistry; 6) to prepare by homologous
recombination, homozygous heparin cofactor II-deficient mice.
The first Specific Aim is based on an observation by the investigator
that for HCII Leu444 Arg, the complex with thrombin can be reversed
if heparin is present, while the complex is stable in the presence of
dermatan sulfate or in the absence of the added cofactor. The data
obtained thus far suggests a model which involves the initial
reversible complex of inhibitor and enzyme to an initially reversible
covalent bond and subsequently to an SDS irreversible covalent bond.
The studies anticipated with this mutant will allow elucidation and
confirmation of this attractive mechanism. In the second Specific Aim,
peptides which mimic the reactive site loop present in all serpins will
be evaluated with respect to their ability to influence HCII inhibitory
functions. Various loop peptides incorporating radiolabels with
different sequences will be used to evaluate the interaction between
the reactive site loop and the beta sheet will be permissible. Using
binding and activity measurement. The peptide will also permit evaluation
of the influence of glycosaminoglycans on the conformational-linkage
between the various states of HCII. An evaluation of thrombin inhibition
by binary complexes of synthetic peptide and HCII in the presence
and absence of glycosaminoglycans will be evaluated using activity
for the formation of covalent complexes with 125[I] thrombin. The third
Specific Aim, tetra- and penta-sulfated hexasacchrides from porcine
skin dermatan sulfate will be evaluated with respect to their
structure and their ability to influence HCII binding and function.
The techniques of approach are fairly common in the identification
of glycosaminoglycan structure involved classical carbohydrate
chemistry. In the further Specific Aim HCII and its complexes will
be subjected to hanging drop crystallization techniques in an attempt
to produce crystals of both the protein and its complexes suitable for
crystallographic evaluation. The fifth and sixth Specific Aims involve
the generation of a murine HCII deficiency model. Studies involve
histochemistry in both human and murine systems to identify the
extravascular sites of HCII. The development of a murine deletion
model by homologous recombination in embryonic stem cells using the
now standard techniques.
描述:确定了六个具体目标。这些包括:1)
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DOUGLAS M TOLLEFSEN其他文献
DOUGLAS M TOLLEFSEN的其他文献
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{{ truncateString('DOUGLAS M TOLLEFSEN', 18)}}的其他基金
Antithrombotic Activity of Ascidian Glycosaminoglycans
海鞘糖胺聚糖的抗血栓活性
- 批准号:
6622188 - 财政年份:2002
- 资助金额:
$ 41.33万 - 项目类别:
Antithrombotic Activity of Ascidian Glycosaminoglycans
海鞘糖胺聚糖的抗血栓活性
- 批准号:
6441300 - 财政年份:2002
- 资助金额:
$ 41.33万 - 项目类别:
Antithrombotic Activity of Ascidian Glycosaminoglycans
海鞘糖胺聚糖的抗血栓活性
- 批准号:
6696337 - 财政年份:2002
- 资助金额:
$ 41.33万 - 项目类别:
Structure and Function of Heparin Cofactor II
肝素辅因子 II 的结构和功能
- 批准号:
7649349 - 财政年份:1996
- 资助金额:
$ 41.33万 - 项目类别:
Structure and Function of Heparin Cofactor II
肝素辅因子 II 的结构和功能
- 批准号:
6763078 - 财政年份:1996
- 资助金额:
$ 41.33万 - 项目类别:
Structure and Function of Heparin Cofactor II
肝素辅因子 II 的结构和功能
- 批准号:
6616222 - 财政年份:1996
- 资助金额:
$ 41.33万 - 项目类别:
STRUCTURE AND FUNCTION OF HEPARIN COFACTOR II
肝素辅因子 II 的结构和功能
- 批准号:
2234112 - 财政年份:1996
- 资助金额:
$ 41.33万 - 项目类别:
Structure and Function of Heparin Cofactor II
肝素辅因子 II 的结构和功能
- 批准号:
7143559 - 财政年份:1996
- 资助金额:
$ 41.33万 - 项目类别:
Structure and Function of Heparin Cofactor II
肝素辅因子 II 的结构和功能
- 批准号:
6543596 - 财政年份:1996
- 资助金额:
$ 41.33万 - 项目类别:
STRUCTURE AND FUNCTION OF HEPARIN COFACTOR II
肝素辅因子 II 的结构和功能
- 批准号:
6184419 - 财政年份:1996
- 资助金额:
$ 41.33万 - 项目类别:
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