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

VL - 62

SP - 88

EP - 92

JO - International Journal of Biochemistry & Cell Biology

JF - International Journal of Biochemistry & Cell Biology

SN - 1357-2725

ER -