Physical Basis for T Cell Receptor Binding and Activity

T 细胞受体结合和活性的物理基础

• 批准号: 8913196
• 负责人: Brian M Baker
• 金额: $ 30.4万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913196
• 关键词: Address; Advanced Development; Affinity; Antibodies; Antigens; Attention; Autoimmune Process; Binding; Binding Sites; Bioinformatics; Biophysics; CD94 Antigen; Cell surface; Cellular Immunity; Chemistry; Clinical; Complex; Data; Databases; Development; Engineering; Epitopes; Fluorescence; Genes; Genetic Engineering; Goals; Immune; Immune system; Immunity; Immunologist; Immunology; Immunotherapy; Kinetics; Knowledge; Ligand Binding; Molecular; Motion; Peptide Signal Sequences; Peptide/MHC Complex; Peptides; Play; Process; Property; Protein Engineering; Proteins; Relative (related person); Resolution; Role; Scanning; Shapes; Signal Transduction; Specificity; Structure; Surface; System; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Thermodynamics; Time; Toxic effect; Translating; Work; X-Ray Crystallography; antigen binding; base; biophysical tools; cancer immunotherapy; cross reactivity; flexibility; imprint; improved; innovation; interfacial; mutant; novel; permissiveness; public health relevance; receptor; receptor binding; research study

DESCRIPTION (provided by applicant): TCR recognition of peptide antigens bound and presented by MHC proteins is a cornerstone of cellular immunity. Although structural knowledge of TCR-pMHC interactions has surged over the past decade, there are significant gaps in our understanding of how TCRs engage pMHC and achieve the key immunological phenomena of specificity, cross-reactivity, and MHC restriction. Indeed, recent years have seen controversy regarding the determinants of TCR recognition properties, such as the extent to which TCRs are evolutionarily biased towards engaging MHC proteins and how such bias may be influenced by other factors. Additionally, structural immunologists are focusing increased attention on molecular motion, which has been shown to have complex and poorly understood influences on specificity, cross-reactivity, and potentially even signaling. Beyond informing basic immunology, an improved understanding of how TCRs achieve specificity, cross-react, and signal is crucial as antigenic epitopes and TCRs begin to be used in clinical settings. This competitive renewal proposal describes an ambitious plan to address key questions related to the issues above, with goals of not only uncovering fundamental principles, but also advancing the development of TCR and pMHC-based therapeutics. There are two broadly complementary specific aims. The first will determine how the distribution of TCR-pMHC binding energy is shaped by evolutionary and non-evolutionary forces. A range of experimental approaches will be applied, including double mutant cycle analyses, X-ray crystallography, protein engineering, and structural bioinformatics. The second aim will establish the role and impact of molecular motion in TCR and pMHC recognition. A range of approaches will again be used, including NMR, fluorescence, and computation. Throughout both aims, a number of novel hypotheses will be tested, including our hypothesis that the TCR binding site has evolved a structural and energetic permissiveness that permits the receptor to adjust to the unique chemistry present in each interface. We will also test the hypotheses that peptide modulation of MHC dynamics influences NK receptor binding, and that alterations in TCR dynamics upon binding contribute to T cell signaling.

描述（由申请人提供）：TCR识别MHC蛋白结合并呈递的肽抗原是细胞免疫的基石。尽管关于TCR-pMHC相互作用的结构知识在过去十年中激增，但我们对tcr如何与pMHC相互作用并实现特异性、交叉反应性和MHC限制等关键免疫现象的理解仍存在重大差距。事实上，近年来关于TCR识别特性的决定因素一直存在争议，例如TCR在进化上偏向MHC蛋白的程度，以及这种偏向如何受到其他因素的影响。此外，结构免疫学家正将更多的注意力集中在分子运动上，分子运动已被证明对特异性、交叉反应性甚至潜在的信号传导具有复杂而知之甚少的影响。随着抗原表位和TCRs开始在临床中使用，除了提供基本的免疫学信息外，对TCRs如何实现特异性、交叉反应和信号传递的更好理解也至关重要。这一竞争性更新提案描述了一项雄心勃勃的计划，旨在解决与上述问题相关的关键问题，其目标不仅是揭示基本原理，而且是推进基于TCR和pmhc的治疗方法的发展。有两个广泛互补的具体目标。第一个将决定TCR-pMHC结合能的分布如何受到进化和非进化力的影响。将应用一系列实验方法，包括双突变周期分析、x射线晶体学、蛋白质工程和结构生物信息学。第二个目标是建立分子运动在TCR和pMHC识别中的作用和影响。一系列的方法将再次被使用，包括核磁共振、荧光和计算。在这两个目标中，将测试一些新的假设，包括我们的假设，即TCR结合位点已经进化出一种结构和能量上的容忍度，允许受体适应每个界面中存在的独特化学物质。我们还将测试MHC动态的肽调节影响NK受体结合的假设，以及结合时TCR动态的改变有助于T细胞信号传导的假设。