Effective disruption of phosphoprotein-protein surface interaction using Zn(II) dipicolylamine-based artificial receptors via two-point interaction
Effective disruption of phosphoprotein-protein surface interaction using Zn(II) dipicolylamine-based artificial receptors via two-point interaction
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DOI：
10.1021/ja056585k
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发表时间：
2006-02-15
影响因子：
15
通讯作者：
Hamachi, I
中科院分区：
文献类型：
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作者：
Ojida, A;Inoue, M;Hamachi, I
蛋白磷酸化在活细胞中普遍存在，它是控制蛋白-蛋白表面相互作用的关键事件之一，在信号转导级联反应中至关重要。我们现在报道，携带双核Zn(ll)-Dpa的小分子受体可以在中性水条件下以交联方式与双磷酸化肽结合，当两个Zn（ll）中心之间的距离可以适当地适应磷酸化肽的两个磷酸基团之间的距离。通过等温滴定量热法（ITC）、诱导CD（圆二色性）和核磁共振（NMR）定量测定了其结合性能。基于这些发现，我们证明了这些类型的小分子能够在微摩尔水平上有效地破坏磷酸化CTD肽和磷酸化蛋白结合结构域Pin1 WW结构域的磷酸化蛋白-蛋白相互作用。基于直接与磷蛋白相互作用的小分子干扰物的策略是独特的，并且在开发磷蛋白-蛋白质相互作用的设计抑制剂方面应该是有希望的。
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(ll)-Dpa can strongly bind to a bisphosphorylated peptide in a cross-linking manner under neutral aqueous conditions when the distance between the two Zn(ll) 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.