It's a tug of war: structure, consequences, and inhibition of CXCR4 and ACKR3 responses to lymphocyte chemoattractant CXCL12
这是一场拉锯战:CXCR4 和 ACKR3 对淋巴细胞趋化剂 CXCL12 反应的结构、后果和抑制
基本信息
- 批准号:10393668
- 负责人:
- 金额:$ 68.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-15 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AMD3100AffectAgonistArchitectureAutoimmune DiseasesBindingBiochemicalBiological AssayBiotinylationBone Marrow Stem Cell TransplantationCXCL12 geneCXCR4 ReceptorsCXCR4 geneCellsChemotactic FactorsClinical ResearchComplementComplexComputer AnalysisComputer ModelsCoupledCouplingCryoelectron MicroscopyCrystallographyDevelopmentDiseaseDown-RegulationDrug TargetingEnvironmentFDA approvedG-Protein-Coupled ReceptorsGTP-Binding ProteinsGoalsHematological DiseaseHematopoietic stem cellsHeterodimerizationHomingImmune responseImmunologic SurveillanceIndividualInflammationInflammatoryInflammatory Bowel DiseasesInvestigationKnowledgeLettersLigandsLymphocyteMass Spectrum AnalysisMediatingModelingModificationMolecularMolecular ConformationMultiple SclerosisMutagenesisNaturePatternPharmacologyPlayPreparationPropertyProteomicsRegulationResolutionRestRheumatoid ArthritisRoentgen RaysRoleSignal TransductionStromal Cell-Derived Factor 1StructureTechniquesTherapeuticTranslatingWarWorkX-Ray Crystallographyantagonistbasebeta-arrestincell motilitychemokinechemokine receptorcohesioncomplement C2adrug discoveryexperimental studyextracellularidiopathic pulmonary fibrosisimprovedinsightmigrationmolecular dynamicsmolecular modelingnovelorgan growthpreclinical studypreventreceptorresponsesmall moleculesmall molecule therapeuticsspatiotemporaltargeted treatmenttherapeutic targettraffickinguptake
项目摘要
The G protein-coupled chemokine receptor, CXCR4, and the atypical chemokine receptor, ACKR3, play critical
roles in cell migration during immune responses and organ development, through coordinated responses to a
shared ligand, CXCL12. Both receptors contribute to numerous inflammatory and autoimmune diseases and are
under active investigation as therapeutic targets. Nevertheless, there is currently only one FDA-approved
CXCR4 antagonist (AMD3100/Plerixafor), and its use is limited to mobilizing hematopoietic stem cells for bone
marrow transplants, because many of its properties are suboptimal. Therapeutic targeting of ACKR3 is at a less
mature stage than CXCR4; in fact, most known compounds are agonists, and it is unclear how to antagonize
this receptor. Improved compounds targeting both CXCR4 and ACKR3 are therefore needed.
As an "atypical" receptor, ACKR3 is widely assumed to function only through β-arrestin (and not G proteins), and
is best known for its ability to “scavenge” CXCL12 from the extracellular environment. By doing so, ACKR3
prevents downregulation of CXCR4 and maintains its responsiveness to CXCL12 gradients. When co-expressed
in the same cell, ACKR3 can also alter CXCR4 signaling and trafficking via heterodimerization, sequestration of
β-arrestin, and other as-yet-undeciphered mechanisms. Given that ACKR3 binds CXCL12 in an architecture
similar to CXCR4, undergoes similar conformational changes upon activation, and shares all of the conserved
G protein-coupling determinants, its presumed Gi incompetency is striking. Even more striking is the exceptional
robustness of ACKR3 activation to ligand and receptor modifications, whereas CXCR4 activation is abrogated
by the subtlest of such changes. Because of this activation-prone nature, most non-chemokine (and even small
molecule) ligands activate ACKR3 association with β-arrestin, with unknown downstream consequences.
Despite the role of the two receptors in disease, the structural and molecular mechanisms underlying their
individual functions and their cellular crosstalk remain elusive. In this MPI proposal, the Handel and Kufareva
labs combine their experimental and computational expertise, respectively, with their in-depth knowledge of
chemokine receptors, to explain the distinct activation mechanisms of CXCR4 (Aim 1) and ACKR3 (Aim 2) from
the standpoint of structure and dynamics, to understand how to inhibit these receptors (Aims 1 and 2), and to
understand how ACKR3 regulates the function of CXCR4 (Aim 3). To achieve these aims, specific mechanistic
hypotheses are probed with a combination of structural (cryo-EM and crystallography), computational (modeling
and MD) and cell-based functional experiments, and complemented by unbiased discovery proteomics. These
studies will deliver unprecedented insight into the function of CXCR4 and ACKR3, which will have a direct impact
on the development of small molecule therapeutics and provide the rationale for blocking one or both receptors.
By revealing general principles, the proposed studies will also advance the understanding and targeting of other
therapeutically important chemokine receptors, which are considered challenging targets.
G蛋白偶联趋化因子受体CXCR4和非典型趋化因子受体ACKR3起着关键作用
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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Tracy M Handel其他文献
Tracy M Handel的其他文献
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{{ truncateString('Tracy M Handel', 18)}}的其他基金
It's a tug of war: structure, consequences, and inhibition of CXCR4 and ACKR3 responses to lymphocyte chemoattractant CXCL12
这是一场拉锯战:CXCR4 和 ACKR3 对淋巴细胞趋化剂 CXCL12 反应的结构、后果和抑制
- 批准号:
10597645 - 财政年份:2021
- 资助金额:
$ 68.29万 - 项目类别:
Signaling circuits that drive cell movement and ligand scavenging by chemokine receptor CCR2
趋化因子受体 CCR2 驱动细胞运动和配体清除的信号通路
- 批准号:
10559615 - 财政年份:2020
- 资助金额:
$ 68.29万 - 项目类别:
Signaling circuits that drive cell movement and ligand scavenging by chemokine receptor CCR2
趋化因子受体 CCR2 驱动细胞运动和配体清除的信号通路
- 批准号:
10727691 - 财政年份:2020
- 资助金额:
$ 68.29万 - 项目类别:
Regulation of the metastasis promoting chemokine receptor ACKR3 by GPCR kinases, Gβγ and arrestins
GPCR 激酶、Gβγ 和抑制蛋白对促进趋化因子受体 ACKR3 的转移的调节
- 批准号:
10627751 - 财政年份:2020
- 资助金额:
$ 68.29万 - 项目类别:
Signaling circuits that drive cell movement and ligand scavenging by chemokine receptor CCR2
趋化因子受体 CCR2 驱动细胞运动和配体清除的信号通路
- 批准号:
10488001 - 财政年份:2020
- 资助金额:
$ 68.29万 - 项目类别:
Regulation of the metastasis promoting chemokine receptor ACKR3 by GPCR kinases, Gβγ and arrestins
GPCR 激酶、Gβγ 和抑制蛋白对促进趋化因子受体 ACKR3 的转移的调节
- 批准号:
10397636 - 财政年份:2020
- 资助金额:
$ 68.29万 - 项目类别:
Signaling circuits that drive cell movement and ligand scavenging by chemokine receptor CCR2
趋化因子受体 CCR2 驱动细胞运动和配体清除的信号通路
- 批准号:
9917599 - 财政年份:2020
- 资助金额:
$ 68.29万 - 项目类别:
Regulation of the metastasis promoting chemokine receptor ACKR3 by GPCR kinases, Gβγ and arrestins
GPCR 激酶、Gβγ 和抑制蛋白对促进趋化因子受体 ACKR3 的转移的调节
- 批准号:
10162570 - 财政年份:2020
- 资助金额:
$ 68.29万 - 项目类别:
Signaling circuits that drive cell movement and ligand scavenging by chemokine receptor CCR2
趋化因子受体 CCR2 驱动细胞运动和配体清除的信号通路
- 批准号:
10360504 - 财政年份:2020
- 资助金额:
$ 68.29万 - 项目类别:
Insights into Activation Mechanisms of G Protein-Coupled and Atypical β-Arrestin-Coupled Chemokine Receptors
深入了解 G 蛋白偶联和非典型 β-抑制蛋白偶联趋化因子受体的激活机制
- 批准号:
9899267 - 财政年份:2019
- 资助金额:
$ 68.29万 - 项目类别:
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