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

Research output: Research - peer-reviewJournal article

  • Longguang Jiang
    Longguang JiangFujian Institute of Research on the Structure of Matter, Chinese Academy of SciencesChina
  • Baoyu Zhao
    Baoyu ZhaoFujian Institute of Research on the Structure of Matter, Chinese Academy of SciencesChina
  • Peng Xu
    Peng XuDenmark
  • Hans Peter Sørensen
    Hans Peter SørensenDenmark
  • Jan K Jensen
  • Anni Christensen
  • Masood Hosseini
    Masood HosseiniDenmark
  • Niels Christian Nielsen
  • Knud J Jensen
    Knud J JensenDepartment of Chemistry, Faculty of Science, University of CopenhagenDanish-Chinese Centre for Proteases and CancerDenmark
  • Peter A. Andreasen
    Peter A. AndreasenDenmark
  • Mingdong Huang
    Mingdong Huang
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 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
StatePublished - May 2015

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