Effective Disruption of Phosphoprotein-Protein Surface Interaction Using Zn(II) Dipicolylamine-Based Artificial Receptors via Two-Point Interaction

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• 作者：Akio Ojida ; Masa-aki Inoue ; Yasuko Mito-oka ; Hiroshi Tsutsumi ; Kazuki Sada ; and Itaru Hamachi
• 刊名：Journal of the American Chemical Society
• 出版年：2006
• 出版时间：February 15, 2006
• 年：2006
• 卷：128
• 期：6
• 页码：2052 - 2058
• 全文大小：186K
• 年卷期：v.128,no.6(February 15, 2006)
• ISSN：1520-5126

文摘

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