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Molecular Basis for the Inhibition of HMGA1 Proteins by Distamycin A

机译：Distamycin A抑制HMGA1蛋白的分子基础

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The molecular mechanism for the displacement of HMGA1 proteins from DNA is integral to disrupting their cellular function, which is linked to many metastatic cancers. Chemical shift and NOESY NMR experiments provide structural evidence for the displacement of an AT hook peptide (DNA binding motif of HMGA1 proteins) by both monomeric and dimeric distamycin. However, the displaced AT hook alters distamycin binding by weakening the distamycin:DNA complex, while slowing monomeric distamycin dissociation when AT hook is in excess. The central role of the AT hook was evaluated by monitoring full-length HMGA1a protein binding using fluorescence anisotropy. HMGA1a was effectively displaced by distamycin, but the cooperative binding exhibited by distamycin was eliminated by displaced HMGA1a. Additionally, these studies indicate that HMGA1a is displaced from the DNA by 1 equiv of distamycin, suggesting the ability to develop therapeutics that take advantage of the positively cooperative nature of HMGA1a binding.
机译：HMGA1蛋白从DNA置换的分子机制是破坏其细胞功能所不可或缺的，这与许多转移性癌症有关。化学位移和NOESY NMR实验为AT钩状肽（HMGA1蛋白的DNA结合基序）被单体和二聚体他霉素置换提供了结构证据。但是，被置换的AT钩会通过削弱Distamycin：DNA复合物来改变二霉素的结合，而当AT钩过多时，会减慢单体DTA的解离。通过使用荧光各向异性监测全长HMGA1a蛋白结合来评估AT钩的核心作用。 HMGA1a有效地被间苯二酚置换，但是间苯二酚显示的协同结合被置换后的HMGA1a消除。此外，这些研究表明，HMGA1a从DNA中被1当量的间他霉素取代，表明开发利用HMGA1a结合的正向合作性质的治疗剂的能力。

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