Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
ACS Chem Biol. 2012 May 18;7(5):817-21. doi: 10.1021/cb200478t. Epub 2012 Feb 15.
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 Å(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.
我们从一个大型的化学约束双环肽组合文库中分离出一种对人尿激酶型纤溶酶原激活物(uPA)具有选择性和高效抑制活性的抑制剂（Ki = 53 nM），并对其复合物进行了结晶。该复合物揭示了肽的扩展结构，两个肽环与靶标结合，形成一个具有 701 Å2 的大相互作用表面，其中有多个氢键和互补的电荷相互作用，解释了抑制剂的高亲和力和特异性。该界面类似于两个蛋白质之间的界面，表明这些约束肽具有作为小蛋白模拟物的潜力。
