Bicyclic Peptide Inhibitor Reveals Large Contact Interface with a Protease Target
Bicyclic Peptide Inhibitor Reveals Large Contact Interface with a Protease Target
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DOI：
10.1021/cb200478t
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发表时间：
2012-05-01
影响因子：
4
通讯作者：
Heinis, Christian
中科院分区：
文献类型：
--
作者：
Angelini, Alessandro;Cendron, Laura;Heinis, Christian
从大量化学约束双环肽组合文库中，我们分离出一种选择性强效（K-i = 53 nM）的人尿激酶型纤溶酶原激活物（uPA）抑制剂，并结晶该复合物。这揭示了肽的扩展结构，两个肽环与靶标结合形成701埃(2)的大相互作用表面，具有多个氢键和互补电荷相互作用，解释了该抑制剂的高亲和力和特异性。界面类似于两种蛋白质之间的界面，这表明这些受约束的肽具有充当小蛋白质模拟物的潜力。
From a large combinatorial library of chemically constrained bicyclic peptides we isolated a selective and potent (K-i = 53 nM) inhibitor of human urokinase-type plasminogen activator (uPA) and crystallized the complex. This revealed an extended structure of the peptide with both peptide loops engaging the target to form a large interaction surface of 701 angstrom(2) with multiple hydrogen bonds and complementary charge interactions, explaining the high affinity and specificity of the inhibitor. The interface resembles that between two proteins and suggests that these constrained peptides have the potential to act as small protein mimics.