The molecular recognition of proteins by antibodies: A m

抗体对蛋白质的分子识别：A m

• 批准号: 7337734
• 负责人: Sandra Smith-Gill
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7337734
• 关键词: molecular; recognition; proteins; antibodies

The Structural Immunology Section investigates molecular recognition in antibody complexes with proteins as model systems to elucidate the general principles of protein target recognition by antibodies. We are using a comparative approach with a set of structurally and functionally related monoclonal antibodies, isolated during the evolution of the antibody immue response to a structurally defined protein antigen, in order to address the following questions about molecular recognition: (i) What structural features are predictive of complex association rates, stabilities, and thermodynamics? How do these functional parameters interrelate? (ii) What roles do electrostatic interactions, hydrophobic interactions, and water play in these processes? (iii) What structural features are predictive of specificity, or cross-reactivity with other antigens? (iv) What structural mechanisms are affected by somatic mutations during the process of antibody affinity maturation as the immune response progresses? (v) What is the influence of engineered constant region segments on binding kinetics and thermodynamics? The results to date have provided new paradigms on the mechanism of antibody-antigen binding, and in addition have provided new methodology for examining these interactions. The thermodynamic studies have revealed properties which we believe to be predictive of binding characteristics including long term complex stability and likely cross-reactivity with related antigens, and we are developing a protocol for assessing these properties which would be valuable in selection of lead therapeutic antibodies. The insight(s) gained by analyses of complex kinetics and thermodynamics provide a framework and rationale for design of antibodies of predefined specificity, and will also lead to better strategies for structure-based drug design and selection of lead compounds in molecular targeting efforts. It also provides a framework for understanding binding of other complexes, including as the HDM2 inhibitors of tumor suppressor p53 protein currently in progress in my group, and chaperone binding to receptors in collaboration with Dr. Wang's group. We are also planning future investigations on the ubiquitin pathway.

结构免疫学部分研究了与蛋白质作为模型系统的抗体复合物中的分子识别，以阐明抗体蛋白靶标识别的一般原理。我们使用的是与一组结构和功能相关的单克隆抗体的比较方法，该抗体在对结构定义的蛋白质抗原的抗体免疫反应的演变过程中分离出来，以解决有关分子识别的以下问题：（i）哪些结构特征可以预测复杂的缔合率率，稳定性，稳定性，稳定性，和热动力学？这些功能参数如何相互关联？ （ii）在这些过程中，静电相互作用，疏水相互作用和水发挥了什么作用？ （iii）哪些结构特征可以预测特异性或与其他抗原的交叉反应性？ （iv）随着免疫反应的进展，在抗体亲和力成熟过程中，哪些结构机制受到体细胞突变的影响？ （v）工程恒定区域段对结合动力学和热力学的影响是什么？迄今为止，结果为抗体 - 抗原结合的机理提供了新的范式，此外，还为检查这些相互作用提供了新的方法。热力学研究揭示了我们认为的特性，这些特性可以预测结合特征，包括长期复杂稳定性和可能与相关抗原的交叉反应性，并且我们正在开发一种评估这些特性的方案，这些属性对于选择铅疗法抗体的有价值。通过对复杂动力学和热力学的分析获得的洞察力为设计预定义特异性的抗体设计提供了一个框架和基本原理，并且还将为基于结构的药物设计和分子靶向工作中铅化合物的选择提供更好的策略。它还提供了理解其他复合物结合的框架，包括作为目前正在进行的肿瘤抑制剂p53蛋白的HDM2抑制剂，以及与王博士的小组合作的伴侣结合与受体的结合。我们还计划对泛素途径进行未来的调查。