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。

基本信息

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
项目类别：
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

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

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项目摘要

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剂与各种疾病相关 - 尤其是癌症，并代表了药物发现的潜在靶标。这 AGPCR B3（ADGRB3）是符合此FOA的列出目标之一。由Pharos数据库识别为具有广泛适用性的高价值热目标，ADGRB3的多域结构，其表达式在多种时间和细胞类型中，其相互作用伙伴强烈表明功能的多效性。然而，作为一种理解的受体，ADRGB3的激活机制，对细胞生理的影响和信号通路仍然是未知的。更具体地说，尚不清楚ADGRB3是否通过配体进行变构调节或细胞外N末端碎片（NTF）中的域间相互作用，导致ADGRB3通过 Stachel系束激动剂。我们的研究计划的中心是大脑中的ADGRB3，众所周知会发生变化神经元的形态和突触健康。我们的实验室研究了ADGRB3及其配体，Synapse 在突触粘合剂和神经元形态变化的背景下组织C1QL蛋白。我们发布了C1QL的第一个晶体结构，并扩展了ADGRB3的突触相互作用网络表明C1QL3介导ADGRB3和神经元五肽之间的第四纪相互作用。我们的理由是对配体C1QL和NTF ADGRB3互动的生物物理理解提供了独特的机会为了形象化其化学和构象，提供了对ADGRB3变构机制的首次见解激活。该建议旨在确定C1QL配体与各种NTF之间的复杂结构 ADGRB3构建体，解密其低聚状态，检查NTF Interyain相互作用并测试ADGRB3 对细胞形态的影响。我们的策略具有创新性，因为它将提供深厚的生物物理理解可以直接在蜂窝情况下进行探测。拟议的研究很重要，因为它给出了坚实的我们的长期目标的基础是设计激动剂或反对者，以瞄准NTF ADGRB3绑定界面。结果将立即产生积极的影响，因为它们直接解决了我们的关键差距了解ADGRB3并提供可推广的分子方法。我们的结果和技术将适用于开发与ADBRB3相关的疾病的疗法。那，它具有一般的巨大潜力提前对一类信号蛋白的生物物理研究和药物操纵为人类健康。