Molecular Mechanisms of G protein-coupled Receptor Biased Signaling
G 蛋白偶联受体偏向信号传导的分子机制
基本信息
- 批准号:10404094
- 负责人:
- 金额:$ 38.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:BindingBiological AssayBiologyCell CommunicationCellsChemicalsDrug TargetingEnergy TransferExhibitsG-Protein-Coupled ReceptorsGTP-Binding ProteinsGenerationsIntegral Membrane ProteinKineticsKnowledgeLaboratoriesLeadLigandsLuciferasesMolecularMonitorMovementMutagenesisPathway interactionsPharmaceutical PreparationsProcessResearchResearch PersonnelSignal PathwaySignal TransductionSignal Transduction PathwayStructureTechniquesTherapeuticbasebeta-arrestinbiophysical techniquesdesignextracellularpreferenceprotein Bprotein functionreceptorreceptor bindingrecruitside effecttargeted treatment
项目摘要
Research Summary
G protein-coupled receptors (GPCRs) are an important superfamily of seven transmembrane proteins involved
in cell-to-cell communication essential for sensing, movement, and thought processes. A significant portion of
current approved drug therapies target GPCRs, but suffer from “on-target” side-effects related to the
engagement of differential signaling pathways known as “functional selectivity” or “biased signaling.” Exploiting
biased signaling represents a promising approach toward designing pathway-selective drugs with better “on-
target” profiles, but the mechanisms at the structural level that lead to biased signaling are still poorly
understood. Recent advancement in structural knowledge of biased ligand recognition has led to the
identification of binding pocket motifs, such as extracellular loop 2 (EL2) and transmembrane (TM) 7, important
for `switching' biased signaling via direct ligand engagement. Using a structure-based approach, my laboratory
aims to use a variety of chemical biology and biophysical approaches to uncover common mechanisms within
the binding pocket that govern biased signaling. Strategies will incorporate a combination of structure-guided
mutagenesis, orthosteric/allosteric biased ligands, kinetic monitoring of G protein function and β-arrestin
recruitment using luciferase and bioluminescent resonance energy transfer (BRET) techniques, and structure-
`functional selectivity' relationships (SFSRs) to ultimately to pin-point key GPCR binding motifs involved in
effector switching. This approach focuses on key receptors where there is structural knowledge and G protein
and β-arrestin-biased ligands available. Through these studies, a comprehensive mechanistic understanding
into GPCR biased signaling will guide researchers toward a new generation of superior therapeutics.
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研究总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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John D McCorvy其他文献
John D McCorvy的其他文献
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{{ truncateString('John D McCorvy', 18)}}的其他基金
Structure-based Design of Selective Serotonin Biased Agonists as Chemical Probes for Psychedelic Potential
基于结构的选择性血清素偏向激动剂设计作为迷幻潜力的化学探针
- 批准号:
10712002 - 财政年份:2023
- 资助金额:
$ 38.5万 - 项目类别:
Molecular Mechanisms of G protein-coupled Receptor Biased Signaling
G 蛋白偶联受体偏向信号传导的分子机制
- 批准号:
10618331 - 财政年份:2019
- 资助金额:
$ 38.5万 - 项目类别:
Molecular Mechanisms of G protein-coupled Receptor Biased Signaling
G 蛋白偶联受体偏向信号传导的分子机制
- 批准号:
10164807 - 财政年份:2019
- 资助金额:
$ 38.5万 - 项目类别:
Molecular Mechanisms of G protein-coupled Receptor Biased Signaling
G 蛋白偶联受体偏向信号传导的分子机制
- 批准号:
9796468 - 财政年份:2019
- 资助金额:
$ 38.5万 - 项目类别:
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