Bicyclic peptide inhibitor reveals large contact interface with a protease target.
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.
Institute of Chemical Sciences and Engineering,  Ecole Polytechnique Fédérale de Lausanne  (EPFL), CH-1015 Lausanne, Switzerland.
Alessandro
A
Angelini
Laura
L
Cendron
Shiyu
S
Chen
Jeremy
J
Touati
Greg
G
Winter
Giuseppe
G
Zanotti
Christian
C
Heinis
D000595:Amino Acid Sequence; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D010455:Peptides; D014568:Urokinase-Type Plasminogen Activator