Effective disruption of phosphoprotein-protein surface interaction using Zn(II) dipicolylamine-based artificial receptors via two-point interaction

Akio Ojida, Masa Aki Inoue, Yasuko Mito-Oka, Hiroshi Tsutsumi, Kazuki Sada, Itaru Hamachi

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Protein phosphorylation is ubiquitously involved in living cells, and it is one of the key events controlling protein-protein surface interactions, which are essential in signal transduction cascades. We now report that the small molecular receptors bearing binuclear Zn(II)-Dpa can strongly bind to a bisphosphorylated peptide in a cross-linking manner under neutral aqueous conditions when the distance between the two Zn(II) centers can appropriately fit in that of the two phosphate groups of the phosphorylated peptide. The binding property was quantitatively determined by ITC (isothermal titration calorimetry), induced CD (circular dichroism), and NMR. On the basis of these findings, we demonstrated that these types of small molecules were able to effectively disrupt the phosphoprotein-protein interaction in a phosphorylated CTD peptide and the Pin1 WW domain, a phosphoprotein binding domain, at a micromolar level. The strategy based on a small molecular disruptor that directly interacts with phosphoprotein is unique and should be promising in developing a designer inhibitor for phosphoprotein-protein interaction.

Original languageEnglish
Pages (from-to)2052-2058
Number of pages7
JournalJournal of the American Chemical Society
Volume128
Issue number6
DOIs
Publication statusPublished - Feb 15 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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