Distinctive binding modes and inhibitory mechanisms of two peptidic inhibitors of urokinase-type plasminogen activator with isomeric P1 residues.
Distinctive binding modes and inhibitory mechanisms of two peptidic inhibitors of urokinase-type plasminogen activator with isomeric P1 residues.
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DOI：
10.1016/j.biocel.2015.02.016
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发表时间：
2015-05
期刊：
影响因子：
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通讯作者：
Longguang Jiang;Baoyu Zhao;Peng Xu;H. P. Sørensen;J. Jensen;A. Christensen;M. Hosseini;N. C. Nielsen;K. Jensen;P. Andreasen;Mingdong Huang
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文献类型：
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作者：
Longguang Jiang;Baoyu Zhao;Peng Xu;H. P. Sørensen;J. Jensen;A. Christensen;M. Hosseini;N. C. Nielsen;K. Jensen;P. Andreasen;Mingdong Huang
两种异构的哌啶衍生物（Meta和帕拉异构体）被用作尿激酶型纤溶酶原激活剂的环肽抑制剂（CPAYSRYLDC）的P1位的精氨酸模拟物。两种所得的环肽显示出对靶酶的极大不同的亲和力（约70倍）。X-射线晶体结构分析表明，两个P1残基插入到S1特异性口袋中，在难以区分的方式。然而，其余的肽以完全不同的方式结合在酶的表面上，尽管序列高度相似，但这两种肽具有不同的构象。这些结果表明P1残基的细微差异如何决定外部位点相互作用和肽抑制剂的效力，并突出了P1残基对蛋白酶抑制的重要性。本研究为开发肽类药物进行药物干预提供了重要信息。
Two isomeric piperidine derivatives (meta and para isomers) were used as arginine mimics in the P1 position of a cyclic peptidic inhibitor (CPAYSRYLDC) of urokinase-type plasminogen activator. The two resulting cyclic peptides showed vastly different affinities (∼70 fold) to the target enzyme. X-ray crystal structure analysis showed that the two P1 residues were inserted into the S1 specificity pocket in indistinguishable manners. However, the rest of the peptides bound in entirely different ways on the surface of the enzyme, and the two peptides have different conformations, despite the highly similar sequence. These results demonstrate how the subtle difference in P1 residue can dictate the exosite interactions and the potencies of peptidic inhibitors, and highlight the importance of the P1 residue for protease inhibition. This study provides important information for the development of peptidic agents for pharmacological intervention.