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

Research output: Contribution to journalLetterResearchpeer-review

  • Longguang Jiang
  • Baoyu Zhao
  • Peng Xu
  • Hans Peter Sørensen
  • Jan Kristian Jensen
  • Anni Christensen
  • Masood Hosseini
  • Niels Christian Nielsen
  • Jensen, Knud Jørgen
  • Peter Andreasen
  • Mingdong 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.

Original languageEnglish
JournalInternational Journal of Biochemistry & Cell Biology
Pages (from-to)88-92
Number of pages5
Publication statusPublished - 2015

ID: 143056442