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Interaction of Thrombin with Sucrose Octasulfate

机译：凝血酶与蔗糖occasulfate的相互作用

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摘要

The serine protease thrombin plays multiple roles in many important physiological processes, especially coagulation, where it functions as both a pro- and anticoagulant. The polyanionic glycosaminoglycan heparin modulates thrombin’s activity through binding at exosite II. Sucrose octasulfate (SOS) is often used as a surrogate for heparin, but it is not known whether it is an effective heparin mimic in its interaction with thrombin. We have characterized the interaction of SOS with thrombin in solution and determined a crystal structure of their complex. SOS binds thrombin with a Kd of ～1.4 μM, comparable to that of the much larger polymeric heparin measured under the same conditions. Nonionic (hydrogen bonding) interactions make a larger contribution to thrombin binding of SOS than to heparin. SOS binding to exosite II inhibits thrombin’s catalytic activity with high potency but with low efficacy. Analytical ultracentrifugation shows that bovine and human thrombins are monomers in solution in the presence of SOS, in contrast to their complexes with heparin, which are dimers. In the X-ray crystal structure, two molecules of SOS are bound nonequivalently to exosite II portions of a thrombin dimer, in contrast to the 1:2 stoichiometry of the heparin?thrombin complex, which has a different monomer association mode in the dimer. SOS and heparin binding to exosite II of thrombin differ on both chemical and structural levels and, perhaps most significantly, in thrombin inhibition. These differences may offer paths to the design of more potent exosite II binding, allosteric small molecules as modulators of thrombin function.
机译：丝氨酸蛋白酶凝血酶在许多重要的生理过程中起多种作用，尤其是凝结，其中它可以作为促凝血剂和抗凝血剂起作用。聚阴离子糖胺聚糖肝素通过在优选II下结合调节凝血酶的活性。蔗糖Octasulfate（SOS）通常用作肝素的替代物，但尚不清楚它是否是血栓其相互作用的有效肝素。我们表征了SOS在溶液中与凝血酶的相互作用，并确定了它们复合物的晶体结构。 SOS将凝血酶结合，具有〜1.4μm的Kd，与在相同条件下测量的更大的聚合物肝素的凝血酶相当。非离子（氢键）相互作用对SOS的凝血酶结合产生更大的贡献，而不是肝素。与exosite II的SOS结合抑制凝血酶的催化活性，具有高效力，但功效低。分析超速分析表明，牛和人血栓形成在SOS存在下溶液中的单体，与其与肝素的络合物相比，这是二聚体的。在X射线晶体结构中，与肝素α络合物的1：2化学算法相反，两种SOS的SOS与凝血酶αααααα蛋白复合物相反，其在二聚体中具有不同的单体缔合模式。 SOS和肝素与凝血酶的exosite II结合的结合在凝血酶抑制中，也许最显着的凝血酶和结构水平不同。这些差异可以提供更有效的曝光性II结合，变构小分子作为凝血酶功能的调节剂的途径。

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  • 来源
    《Biochemistry》 |2011年第32期|共10页
  • 作者

    Bijoy J. Desai; Rio S. Boothello; Akul Y. Mehta; J. Neel Scarsdale; H. Tonie Wright; Umesh R. Desai;

  • 作者单位

    Departments of Medicinal Chemistry and Biochemistry and Institute for Structural Biology and Drug Discovery Virginia Commonwealth University 800 East Leigh Street Suite 212 Richmond Virginia 23219 United States;

    Departments of Medicinal Chemistry and Biochemistry and Institute for Structural Biology and Drug Discovery Virginia Commonwealth University 800 East Leigh Street Suite 212 Richmond Virginia 23219 United States;

    Departments of Medicinal Chemistry and Biochemistry and Institute for Structural Biology and Drug Discovery Virginia Commonwealth University 800 East Leigh Street Suite 212 Richmond Virginia 23219 United States;

    Departments of Medicinal Chemistry and Biochemistry and Institute for Structural Biology and Drug Discovery Virginia Commonwealth University 800 East Leigh Street Suite 212 Richmond Virginia 23219 United States;

    Departments of Medicinal Chemistry and Biochemistry and Institute for Structural Biology and Drug Discovery Virginia Commonwealth University 800 East Leigh Street Suite 212 Richmond Virginia 23219 United States;

    Departments of Medicinal Chemistry and Biochemistry and Institute for Structural Biology and Drug Discovery Virginia Commonwealth University 800 East Leigh Street Suite 212 Richmond Virginia 23219 United States;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

    Thrombin; Interaction; Sucrose;

    机译：凝血酶;相互作用;蔗糖;

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