Antiangiogenic forms of antithrombin specifically bind to the anticoagulant heparin sequence.
Antiangiogenic forms of antithrombin specifically bind to the anticoagulant heparin sequence.
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DOI：
10.1021/bi801656u
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发表时间：
2008-12-23
期刊：
影响因子：
2.9
通讯作者：
Olson ST
中科院分区：
文献类型：
--
作者：
Schedin-Weiss S;Richard B;Hjelm R;Olson ST
肝素的特定五糖序列与天然抗凝血酶具有高亲和力结合，并通过先前描述的两步相互作用机制诱导抑制剂的构象变化。在这项工作中，相互作用的肝素与抗血管生成的潜伏和切割的抗凝血酶形式进行了研究。肝素与这些抗凝血酶形式的结合对于与天然抗凝血酶相同的五糖序列是特异性的。快速动力学研究表明，这五糖诱导的构象变化也在潜伏和裂解抗凝血酶。与天然抗凝血酶相比，这些抗凝血酶形式对五糖的结合亲和力低约30倍，这是由于离子相互作用少2-3个，导致构象改变状态不太稳定。潜在的和切割的抗凝血酶的亲和力较长的肝素链，含有五糖序列，是两倍低于五糖本身。这与天然抗凝血酶的相互作用形成对比，并表明肝素的五糖序列侧翼的残基被潜在的和切割的形式排斥。这些发现有助于阐明肝素或硫酸乙酰肝素介导抗凝血酶抗血管生成活性的机制。
A specific pentasaccharide sequence of heparin binds with high affinity to native antithrombin and induces a conformational change in the inhibitor by a previously described two-step interaction mechanism. In this work, the interactions of heparin with the antiangiogenic latent and cleaved antithrombin forms were studied. Binding of heparin to these antithrombin forms was specific for the same pentasaccharide sequence as native antithrombin. Rapid kinetics studies demonstrated that this pentasaccharide induced a conformational change also in latent and cleaved antithrombin. The binding affinities of these antithrombin forms for the pentasaccharide, as compared to native antithrombin, were ∼30-fold lower due to 2-3 fewer ionic interactions, resulting in less stable conformationally altered states. Affinities of latent and cleaved antithrombin for longer heparin chains, containing the pentasaccharide sequence, were two-fold lower than for the pentasaccharide itself. This contrasts the interaction with native antithrombin and demonstrates that residues flanking the pentasaccharide sequence of heparin are repelled by the latent and cleaved forms. These findings contribute to delineating the mechanism by which heparin or heparan sulfate mediate antiangiogenic activity of antithrombin.
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影响因子：
2.9
作者：
Hjelm, Rebecka;Schedin-Weiss, Sophia
通讯作者：
Schedin-Weiss, Sophia
影响因子：
56.9
作者：
O'Reilly, MS;Pirie-Shepherd, S;Folkman, J
通讯作者：
Folkman, J
影响因子：
2.9
作者：
NORDENMAN, B;BJORK, I
通讯作者：
BJORK, I
影响因子：
4.8
作者：
dela Cruz, Richard Glenn C.;Jairajpuri, Mohamad Aman;Bock, Susan C.
通讯作者：
Bock, Susan C.
DOI：
10.1111/j.1432-1033.1978.tb12568.x
发表时间：
1978-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
DANIELSSON, A;BJORK, I
通讯作者：
BJORK, I