Myc及其他b-HLH-ZIP蛋白识别DNA的结构限制：癌蛋白类似物的设计
Structural constraints for DNA recognition by Myc and other b-HLH-ZIP proteins: design of oncoprotein analogues.
作者信息
Takemoto C, Fisher D E
机构信息
Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Gene Expr. 1995;4(6):311-7.
DNA recognition is a critical property of many transcription factors, some of which play important roles in human disease. Disruption of this recognition may profoundly influence the biology of these factors. One such factor, the Myc oncoprotein, utilizes a basic/helix-loop-helix/leucine zipper motif to recognize the DNA target CACGTG. As discussed here, this recognition appears to occur through recognition by one face of a basic region alpha helix utilizing amino acid side chains highly conserved among CACGTG binding proteins. This basic domain alpha helix, however, requires DNA binding for stabilization. To circumvent this energetic requirement, analogues were produced that introduce multiple alanines, displaying substantially increased spontaneous alpha helicity and significantly enhanced DNA affinity. These studies simplify our understanding of the structural constraints for DNA recognition by this family and may serve as a template for the design of small molecule transcription-targeted therapeutics.
DNA识别是许多转录因子的关键特性，其中一些在人类疾病中发挥重要作用。这种识别的破坏可能会深刻影响这些因子的生物学特性。一种这样的因子，即Myc癌蛋白，利用一个碱性/螺旋-环-螺旋/亮氨酸拉链基序来识别DNA靶序列CACGTG。如本文所讨论的，这种识别似乎是通过碱性区域α螺旋的一个面利用在CACGTG结合蛋白中高度保守的氨基酸侧链进行识别。然而，这个碱性结构域α螺旋需要DNA结合来稳定。为了规避这种能量需求，制备了引入多个丙氨酸的类似物，这些类似物显示出显著增加的自发α螺旋度和显著增强的DNA亲和力。这些研究简化了我们对该家族DNA识别结构限制的理解，并可能作为设计小分子转录靶向治疗药物的模板。
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