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

HMG Box是一种新的小沟DNA识别基序，它定义了一种新的 不同种类的核蛋白。 对人类特别重要 生物学是HMG转录因子，其调节基本功能 在免疫系统中（淋巴特异性调节剂TCR 1和LEF 1）， 代谢（胰岛素应答转录因子IREBP 1），和男性 性发育（睾丸决定因子SRY）。 在此，我们建议 进行多维核磁共振研究之间的一个特定的复杂的 代表性的HMG盒（SRY）及其DNA结合位点。 这些研究将 测试以下假设; 假设1. 序列特异性HMG盒显示了一种新的机制， DNA识别 假设2. 在HMG结合时，DNA经历了重大的结构变化。 假设3. HMG盒中保守残基的突变改变了蛋白质 结构、稳定性或DNA结合。 假设4. 一种共同的机制是双链DNA识别和 与4路DNA连接的序列独立但结构特异性结合。 结构-功能关系将从比较NMR推断 SRY基因突变与人类发育异常相关的研究。 因此，这种应用提供了将NMR应用于生物化学的令人兴奋的前景。 人类遗传疾病的分子分析。

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.