Bicyclic Peptide Inhibitor Reveals Large Interface with a Protease Target. From a large combinatorial library of chemically constrained bicyclic peptides, the group of Christian Heinis (Laboratory of Therapeutic Proteins and Peptides - LPPT) isolated a selective and potent (Ki = 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 Å2 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. Alessandro Angelini et al. ACS Chem. Biol.
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