Peptide mimetics of the thrombin-bound structure of fibrinopeptide A.
Peptide mimetics of the thrombin-bound structure of fibrinopeptide A.
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纤维蛋白肽 A 的凝血酶结合结构的肽模拟物。
DOI：
10.1073/pnas.89.5.1705
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发表时间：
1992
影响因子：
11.1
通讯作者：
Kahn,M
中科院分区：
文献类型：
--
作者：
Nakanishi,H;Chrusciel,RA;Shen,R;Bertenshaw,S;Johnson,ME;Rydel,TJ;Tulinsky,A;Kahn,M
最近的工作表明，纤维蛋白肽A的凝血酶结合构象表现出链-转角-链基序，其中β-转角以残基Glu-11和Gly-12为中心。我们的分子建模分析表明，已发表的纤维蛋白肽构象不能合理地结合到凝血酶，但通过与牛胰蛋白酶抑制剂对齐的两个残基的重新取向提供了一个很好的适合在深凝血酶裂缝，并满足所有的实验核Overhauser效应数据。基于这一分析，我们已经成功地设计和合成了杂合肽模拟底物和抑制剂，模拟拟议的β-转角结构。结果表明，转角构象是凝血酶特异性的一个重要方面，我们的转角模拟物设计成功地模拟了纤维蛋白肽的凝血酶结合构象。
Recent work has suggested that the thrombin-bound conformation of fibrinopeptide A exhibits a strand-turn-strand motif, with a beta-turn centered at residues Glu-11 and Gly-12. Our molecular modeling analysis indicates that the published fibrinopeptide conformation cannot bind reasonably to thrombin but that reorientation of two residues by alignment with bovine pancreatic trypsin inhibitor provides a good fit within the deep thrombin cleft and satisfies all of the experimental nuclear Overhauser effect data. Based on this analysis, we have successfully designed and synthesized hybrid peptide mimetic substrates and inhibitors that mimic the proposed beta-turn structure. The results indicate that the turn conformation is an important aspect of thrombin specificity and that our turn mimetic design successfully mimics the thrombin-bound conformation of fibrinopeptide.