Molecular Basis of Biological Recognition and Assembly

该计划项目代表了加州大学洛杉矶分校的八名科学研究人员组成的持续联盟，他们都在一起工作，使用X射线结晶学、核磁共振、电子顺磁共振或计算方法来分析识别的结构基础。八人中有三人是联合首席调查员，五人是参与研究的科学家(主要是因为预算原因)。该项目需要解决的具体问题包括：(1)双组分细菌信号级联的反应调节器NarL和Narp如何通过磷酸化激活DNA结合，以及它们如何识别和结合其特定的基因控制点。(2)DNA的碱基序列和几何形状如何决定其与蛋白质和药物的结合，包括艾滋病病毒逆转录酶的抑制剂和并排的小沟槽结合分子。(3)如何使用完全测序的基因组来识别大分子和以前未描述的蛋白质组合的相互作用网络。(4)结构域交换如何影响蛋白质聚集，以及它是否参与了淀粉样蛋白状态的建立。(5)开发一种设计自组装蛋白质的新方法，并了解设计原理与包括笼子和细丝在内的生物组装的关系。(6)真核细胞谷氨酰胺合成酶结构的测定，作为抗结核药物开发的一步，以及对蛋白质-配体识别的理解。尽管这三个Co-PI的项目清单是不同的，但贯穿所有这些项目的共同线索是，局部结构控制着大分子之间的相互作用，一个分子与另一个分子的识别是建立更大的功能分子间组装的关键步骤。由于空间的限制，参与的科学家的项目无法在这里讨论，但他们的目标是相似的。

This Program Project represents an ongoing consortium of eight scientific investigators at UCLA, all of whom work together in using X-ray crystallography, NMR, EPR, or computational methods to analyze the structural basis for recognition. Three of the eight are Co-Principal Investigators and five are Participating Scientists (primarily for budgetary reasons). Specific problems to be addressed by the Project include: (1) How NarL and NarP, the response regulators of two-component bacterial signaling cascades, are activated for DNA binding by phosphorylation, and how they recognize and bind to their specific gene control sites. (2) How the base sequence and geometry of DNA dictate its binding to proteins and drugs, including inhibitors of the AIDS virus reverse transcriptase and side-by-side minor groove binding molecules. (3) How fully sequenced genomes an be used to identify interacting networks of macromolecules and previously uncharacterized protein assemblies. (4) How domain swapping influences protein aggregation, and whether it is involved in building the amyloid state. (5) Developing a new method for designing self-assembling proteins, and understanding how the design principles relate to biological assemblies, including cages and filaments. (6) Determination of the structure of eukaryotic glutamine synthetase as a step toward development of an anti-tuberculosis drug, and understanding of protein-ligand recognition. Although this list of projects by the three Co-PIs is diverse, the common thread through them all is that local structure controls interactions between macromolecules, and that recognition of one molecule by another is an essential step in the building of larger functional intermolecular assemblies. Space limitations prevent discussion of projects of Participating Scientists here, but their goals are similar.