NRM STUDIES OF AN HMG BOX--A NOVEL DNA-BINDING MOTIF

HMG盒是一种新的小槽DNA识别基序，它定义了一个 核蛋白种类繁多。对人类具有特别重要的意义 生物是HMG转录因子，调节必要的功能 在免疫系统中(淋巴特异性调节因子TCR1和LEF1)， 代谢(胰岛素反应转录因子IREBP1)，男性 性发育(睾丸决定因素SRY)。在此，我们建议 进行特定络合物的多维核磁共振研究 具有代表性的HMG盒(SRY)及其DNA结合位点。这些研究将 检验以下假设； 假设1.序列特异性HMG-Box显示出一种新的机制 DNA识别。 假设2.关于HMG结合，DNA经历了一个主要的结构变化。 假设3：HMG盒中保守残基的突变改变蛋白质 结构、稳定性或DNA结合。 假设4。一个共同的机制是双链DNA识别和 序列无关但结构特异的与4向DNA连接的结合。 结构-功能关系将从比较核磁共振中推断出来 SRY突变与人类发育异常相关的研究。 因此，这一应用提供了将核磁共振应用于 人类遗传性疾病的分子分析。

The HMG Box, a novel motif of minor-groove DNA recognition, defines a diverse class of nuclear proteins. Of particular importance in human biology are HMG transcription factors, which regulate essential functions in the immune system (lymphoid-specific regulators TCR1 and LEF1), metabolism (insulin-responsive transcription factor IREBP1), and male sexual developemnt (testis determining factor SRY). Here we propose to conduct multidimensional NMR studies of a specific complex between a representative HMG Box (SRY) and its DNA binding site. These studies will test the following hypotheses; Hypothesis 1. The sequence-specific HMG-Box exhibits a novel mechanism of DNA recognition. Hypothesis 2. On HMG binding, DNA undergoes a major structural change . Hypothesis 3. Mutation of conserved residues in the HMG Box alters protein structure, stability, or DNA-binding. Hypothesis 4. A common mechanism underlies both duplex DNA recognition and sequence-independent but structure-specific binding to 4-way DNA junctions. Structure-function relationships will be inferred from comparative NMR studies of SRY mutations associated with human developmental abnormalities. This application thus offers the exciting prospect of applying NMR to the molecular analysis of human genetic disorders.