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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

  • Longguang Jiang, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Kina
  • Baoyu Zhao, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Kina
  • Peng Xu, Danmark
  • Hans Peter Sørensen, Danmark
  • Jan K Jensen
  • Anni Christensen
  • Masood Hosseini, Danmark
  • Niels Christian Nielsen
  • Knud J Jensen, Department of Chemistry, Faculty of Science, University of Copenhagen, Danish-Chinese Centre for Proteases and Cancer, Danmark
  • Peter A. Andreasen, Danmark
  • 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.
OriginalsprogEngelsk
TidsskriftInternational Journal of Biochemistry & Cell Biology
Vol/bind62
Sider (fra-til)88-92
Antal sider5
ISSN1357-2725
DOI
StatusUdgivet - maj 2015

Bibliografisk note

inegen

    Forskningsområder

  • proteaser-cancer-isomeri - Røntgenkrystal strukturanalyse

Se relationer på Aarhus Universitet Citationsformater

ID: 85405367