TY - JOUR
T1 - Distinctive binding modes and inhibitory mechanisms of two peptidic inhibitors of urokinase-type plasminogen activator with isomeric P1 residues
AU - Jiang, Longguang
AU - Zhao, Baoyu
AU - Xu, Peng
AU - Sørensen, Hans Peter
AU - Jensen, Jan Kristian
AU - Christensen, Anni
AU - Hosseini, Masood
AU - Nielsen, Niels Christian
AU - Jensen, Knud Jørgen
AU - Andreasen, Peter
AU - Huang, Mingdong
PY - 2015
Y1 - 2015
N2 - Abstract Two isomeric piperidine derivatives (meta and para isomers) were used as arginine mimics in the P1 position of a cyclic peptidic inhibitor (CPAYSRYLDC) of urokinase-type plasminogen activator. The two resulting cyclic peptides showed vastly different affinities (∼70 fold) to the target enzyme. X-ray crystal structure analysis showed that the two P1 residues were inserted into the S1 specificity pocket in indistinguishable manners. However, the rest of the peptides bound in entirely different ways on the surface of the enzyme, and the two peptides have different conformations, despite the highly similar sequence. These results demonstrate how the subtle difference in P1 residue can dictate the exosite interactions and the potencies of peptidic inhibitors, and highlight the importance of the P1 residue for protease inhibition. This study provides important information for the development of peptidic agents for pharmacological intervention.
AB - Abstract Two isomeric piperidine derivatives (meta and para isomers) were used as arginine mimics in the P1 position of a cyclic peptidic inhibitor (CPAYSRYLDC) of urokinase-type plasminogen activator. The two resulting cyclic peptides showed vastly different affinities (∼70 fold) to the target enzyme. X-ray crystal structure analysis showed that the two P1 residues were inserted into the S1 specificity pocket in indistinguishable manners. However, the rest of the peptides bound in entirely different ways on the surface of the enzyme, and the two peptides have different conformations, despite the highly similar sequence. These results demonstrate how the subtle difference in P1 residue can dictate the exosite interactions and the potencies of peptidic inhibitors, and highlight the importance of the P1 residue for protease inhibition. This study provides important information for the development of peptidic agents for pharmacological intervention.
KW - Cyclic peptide
KW - Inhibitor
KW - Protease
KW - Urokinase
KW - X-ray crystal structure
U2 - 10.1016/j.biocel.2015.02.016
DO - 10.1016/j.biocel.2015.02.016
M3 - Letter
C2 - 25744057
AN - SCOPUS:84924858566
SN - 1357-2725
VL - 62
SP - 88
EP - 92
JO - International Journal of Biochemistry & Cell Biology
JF - International Journal of Biochemistry & Cell Biology
ER -