Molecular Basis of Biological Recognition and Assembly

该项目由加州大学洛杉矶分校的八名科学研究人员组成，他们共同使用x射线晶体学、核磁共振、EPR或计算方法来分析识别的结构基础。8人中有3人是联合首席研究员，5人是参与科学家（主要是出于预算原因）。该项目需要解决的具体问题包括：(1)细菌双组分信号级联反应调控因子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位点。(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抑制剂和并排的次要凹槽结合分子。(3)完全测序的基因组如何用于鉴定大分子和以前未表征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，是否参与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，并了解设计原则如何与生物组装（包括笼和细丝）相关。(6)确定真核生物谷氨酰胺合成酶的结构，为开发抗结核药物迈出一步，并了解蛋白质配体识别。虽然这三个co - pi的项目清单各不相同，但贯穿它们的共同点是，局部结构控制着大分子之间的相互作用，而一个分子被另一个分子识别是构建更大的功能分子间组装的必要步骤。由于篇幅限制，无法在这里讨论参与科学家的项目，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.