The biophysical basis of the ADGRB3 extra-cellular interaction network.

ADGRB3 细胞外相互作用网络的生物物理学基础。

• 批准号: 10667127
• 负责人: Susanne Ressl
• 金额: $ 15.21万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667127
• 关键词: Address; Adhesions; Agonist; Allosteric Regulation; Architecture; Area; Binding; Binding Proteins; Biochemical; Biological Assay; Biophysics; Blood coagulation; Brain; Cell Line; Cell physiology; Cells; Cellular Morphology; Chemistry; Complement; Complex; Cryoelectron Microscopy; Databases; Dendrites; Developmental Process; Disease; Dissociation; Drug Targeting; Eligibility Determination; Foundations; Funding; Future; G-Protein-Coupled Receptors; Genome; Goals; Health; Human; Individual; Investigation; Isomerism; Laboratories; Ligands; Link; Location; Malignant Neoplasms; Mammalian Cell; Mediating; Modality; Modeling; Molecular; Molecular Conformation; Morphology; Muscle; Muscular Dystrophies; Mutation; N-terminal; Neurons; Pharmacologic Substance; Protein Family; Protein Secretion; Proteins; Proteolysis; Publishing; Receptor Activation; Research; Signal Pathway; Signal Transduction; Signaling Protein; Site; Solid; Structure; Synapses; Techniques; Testing; Therapeutic; Tin; Tissues; Transmembrane Domain; Visualization; Work; adhesion receptor; antagonist; cell type; design; drug development; drug discovery; experimental study; extracellular; injury and repair; innovation; insight; mutant; neuronal pentraxin; neuropsychiatric disorder; overexpression; pleiotropism; programs; receptor; success; therapeutic target

PROJECT SUMMARY Adhesion G protein-coupled receptors (aGPCR) are important regulators of conserved developmental processes associated with various diseases - especially cancers and represent potential targets for drug discovery. The aGPCR B3 (ADGRB3) is one of the listed targets eligible for this FOA. Identified by the Pharos database as a high-value therapeutic target with broad applicability, the multi-domain architecture of ADGRB3, its expression in multiple tissues and cell types, and its interaction partners strongly suggest a pleiotropy of function. However, as an understudied receptor, ADRGB3’s activation mechanism, impact on cell physiology, and signaling pathway remains largely unknown. More specifically, it is unknown whether ADGRB3 is allosterically regulated via ligand or interdomain interactions in extracellular N-terminal fragment (NTF), leading to ADGRB3 activation via the Stachel tethered agonist. Central to our research program is ADGRB3 in the brain, where it is known to change neuron morphology and synapse health. Our laboratory has studied ADGRB3 and its ligands, the synapse organizing C1QL proteins, in the context of synapse adhesion and neuronal morphological changes. We published the first crystal structures of C1QLs and expanded the synaptic interaction network of ADGRB3 by showing that C1QL3 mediates a quaternary interaction between ADGRB3 and neuronal pentraxins. Our rationale is that the biophysical understanding of ligand C1QL and NTF ADGRB3 interactions offers a unique opportunity to visualize their chemistry and conformation, providing first insights into the ADGRB3 allosteric mechanism of activation. This proposal aims to determine complex structures between C1QL ligands and various NTF ADGRB3 constructs, decipher their oligomeric states, examine NTF interdomain interactions, and test ADGRB3 impact on cell morphology. Our strategy is innovative because it will provide a deep biophysical understanding that can be directly probed in a cellular context. The proposed research is significant because it gives a solid foundation for our longer-term goal of designing agonists or antagonists to target the NTF ADGRB3 binding interface. The results will have an immediate positive impact as they directly address critical gaps in our understanding of ADGRB3 and provide a generalizable molecular approach. Our results and techniques will apply to developing therapeutics for diseases linked to ADBRB3. Thus, it has enormous potential to generally advance biophysical investigations and pharmaceutical manipulation of a class of signaling proteins necessary for human health.

项目摘要 粘附G蛋白偶联受体（aGPCR）是保守发育过程的重要调节因子 与各种疾病相关-特别是癌症，并且代表药物发现的潜在靶点。的 aGPCR B3（ADGRB 3）是符合本FOA条件的列出靶标之一。被Pharos数据库识别为 具有广泛适用性的高价值治疗靶点，ADGRB 3的多结构域结构，其表达 在多种组织和细胞类型中，其相互作用伴侣强烈表明功能的多效性。然而，在这方面， 作为一种未充分研究的受体，ADRGB 3的激活机制、对细胞生理学的影响和信号通路 仍然是未知的。更具体地说，尚不清楚ADGRB 3是否通过配体变构调节， 或细胞外N-末端片段（NTF）中的结构域间相互作用，导致ADGRB 3通过 Stachel系留激动剂。我们研究计划的核心是大脑中的ADGRB 3， 神经元形态和突触健康。我们的实验室研究了ADGRB 3及其配体，突触 组织C1 QL蛋白，在突触粘附和神经元形态学变化的背景下。我们 发表了C1 QLs的第一个晶体结构，并通过以下方式扩展了ADGRB 3的突触相互作用网络： 表明C1 QL 3介导ADGRB 3和神经元正五角蛋白之间的四级相互作用。我们的理据 配体C1 QL和NTF ADGRB 3相互作用的生物物理学理解提供了一个独特的机会， 可视化它们的化学和构象，提供了对ADGRB 3变构机制的第一个见解， activation.该建议旨在确定C1 QL配体和各种NTF之间的复杂结构 ADGRB 3构建体，破译其寡聚状态，检查NTF结构域间相互作用，并测试ADGRB 3 对细胞形态的影响我们的战略是创新的，因为它将提供一个深刻的生物物理理解 可以直接在细胞环境中探测。这项研究的重要性在于它提供了一个坚实的 这为我们设计靶向NTF ADGRB 3结合的激动剂或拮抗剂的长期目标奠定了基础 接口.这些结果将产生直接的积极影响，因为它们直接解决了我们国家 了解ADGRB 3并提供可推广的分子方法。我们的成果和技术将 适用于开发与ADBRB 3相关疾病的治疗方法。因此，它具有巨大的潜力， 先进的生物物理研究和药物操纵一类信号蛋白的必要 为了人类健康。