From a large combinatorial library of chemically 12 constrained bicyclic peptides we isolated a selective and potent 13 (Ki = 53 nM) inhibitor of human urokinase-type plasminogen 14 activator (uPA) and crystallized the complex. This revealed an 15 extended structure of the peptide with both peptide loops 16 engaging the target to form a large interaction surface of 701 Å2 17 with multiple hydrogen bonds and complementary charge 18 interactions, explaining the high affinity and specificity of the 19 inhibitor. The interface resembles that between two proteins 20 and suggests that these constrained peptides have the potential 21 to act as small protein mimics.

Bicyclic Peptide Inhibitor Reveals Large Contact Interface with a Protease Target

CENDRON, LAURA;ZANOTTI, GIUSEPPE;
2012

Abstract

From a large combinatorial library of chemically 12 constrained bicyclic peptides we isolated a selective and potent 13 (Ki = 53 nM) inhibitor of human urokinase-type plasminogen 14 activator (uPA) and crystallized the complex. This revealed an 15 extended structure of the peptide with both peptide loops 16 engaging the target to form a large interaction surface of 701 Å2 17 with multiple hydrogen bonds and complementary charge 18 interactions, explaining the high affinity and specificity of the 19 inhibitor. The interface resembles that between two proteins 20 and suggests that these constrained peptides have the potential 21 to act as small protein mimics.
2012
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/2503080
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