Distinctive binding modes and inhibitory mechanisms of two peptidic inhibitors of urokinase-type plasminogen activator with isomeric P1 residues

The International Journal of Biochemistry & Cell Biology
Longguang JiangMingdong Huang

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.

References

Jul 3, 1997·International Journal of Cancer. Journal International Du Cancer·P A AndreasenM J Duffy
Apr 13, 2000·Nature·M S DennisR A Lazarus
Aug 19, 2000·Cellular and Molecular Life Sciences : CMLS·P A AndreasenH H Petersen
May 22, 2001·Cellular and Molecular Life Sciences : CMLS·B Walker, J F Lynas
Oct 9, 2002·Current Pharmaceutical Design·T W RockwayV L Giranda
Dec 12, 2002·Chemical Reviews·Lizbeth Hedstrom
Jul 3, 2003·Nature Reviews. Genetics·Xose S PuenteCarlos López-Otín
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Mar 11, 2006·The Journal of Biological Chemistry·Can HekimUlf-Håkan Stenman
Aug 8, 2007·Journal of Molecular Biology·Evgeny Krissinel, Kim Henrick
Aug 19, 2007·Journal of Structural Biology·Gengxiang ZhaoMingdong Huang
Jun 2, 2009·Nature Chemical Biology·Christian HeinisGreg Winter
Feb 5, 2010·Biological Chemistry·Ping WuHannu Koistinen
May 11, 2010·PloS One·Katarina HajdinMichele Bernasconi
Jan 5, 2011·The Journal of Biological Chemistry·Zhonghui LinMingdong Huang
Aug 2, 2011·Journal of Molecular Biology·Longguang JiangPeter A Andreasen

❮ Previous
Next ❯

Related Concepts

Related Feeds

Barrel cortex

Here is the latest research on barrel cortex, a region of somatosensory and motor corticies in the brain, which are used by animals that rely on whiskers for world exploration.