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:
- 金额:$ 15.21万
- 依托单位:
- 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:
- 关键词:AddressAdhesionsAgonistAllosteric RegulationArchitectureAreaBindingBinding ProteinsBiochemicalBiological AssayBiophysicsBlood coagulationBrainCell LineCell physiologyCellsCellular MorphologyChemistryComplementComplexCryoelectron MicroscopyDatabasesDendritesDevelopmental ProcessDiseaseDissociationDrug TargetingEligibility DeterminationFoundationsFundingFutureG-Protein-Coupled ReceptorsGenomeGoalsHealthHumanIndividualInvestigationIsomerismLaboratoriesLigandsLinkLocationMalignant NeoplasmsMammalian CellMediatingModalityModelingMolecularMolecular ConformationMorphologyMuscleMuscular DystrophiesMutationN-terminalNeuronsPharmacologic SubstanceProtein FamilyProtein SecretionProteinsProteolysisPublishingReceptor ActivationResearchSignal PathwaySignal TransductionSignaling ProteinSiteSolidStructureSynapsesTechniquesTestingTherapeuticTinTissuesTransmembrane DomainVisualizationWorkadhesion receptorantagonistcell typedesigndrug developmentdrug discoveryexperimental studyextracellularinjury and repairinnovationinsightmutantneuronal pentraxinneuropsychiatric disorderoverexpressionpleiotropismprogramsreceptorsuccesstherapeutic target
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.
项目概要
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(尤其是癌症)相关,是药物发现的潜在目标。
aGPCR B3 (ADGRB3) 是 Pharos 数据库确定的符合该 FOA 的目标之一。
具有广泛适用性的高价值治疗靶点,ADGRB3的多域结构及其表达
在多种组织和细胞类型中,其相互作用伙伴强烈表明其具有多效性功能。
作为一种未被充分研究的受体,ADRGB3的激活机制、对细胞生理学的影响和信号通路
更具体地说,尚不清楚 ADGRB3 是否通过配体进行变构调节。
或胞外 N 端片段 (NTF) 中的域间相互作用,通过
Stachel 系留激动剂是我们研究项目的核心是大脑中的 ADGRB3,已知它会在大脑中发生变化。
我们的实验室研究了 ADGRB3 及其配体突触。
在突触粘附和神经元形态变化的背景下组织 C1QL 蛋白。
发表了第一个 C1QL 的晶体结构,并扩展了 ADGRB3 的突触相互作用网络
显示 C1QL3 介导 ADGRB3 和神经元五聚蛋白之间的四元相互作用。
是对配体 C1QL 和 NTF ADGRB3 相互作用的生物物理学理解提供了独特的机会
可视化它们的化学和构象,提供对 ADGRB3 变构机制的初步见解
该提案旨在确定 C1QL 配体和各种 NTF 之间的复杂结构。
ADGRB3 构建体、破译其寡聚状态、检查 NTF 域间相互作用并测试 ADGRB3
我们的策略是创新的,因为它将提供深入的生物物理学理解。
可以在细胞环境中直接探测,这项研究意义重大,因为它提供了可靠的证据。
为我们设计针对 NTF ADGRB3 结合的激动剂或拮抗剂的长期目标奠定了基础
结果将立即产生积极影响,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。
因此,它具有广泛应用的巨大潜力。
一类信号蛋白的生物物理研究和药物操作的进展是必要的
为了人类的健康。
项目成果
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