Structural Biology of Dopamine Signaling

多巴胺信号传导的结构生物学

基本信息

  • 批准号:
    10322399
  • 负责人:
  • 金额:
    --
  • 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:
    2021-01-01 至 2022-01-02
  • 项目状态:
    已结题

项目摘要

Abstract Human dopamine signaling pathway induces and facilitates dopamine neurotransmission through the mesolimbic dopaminergic pathway, which modifies reward-related behaviors and is associated with the development of many diseases, including schizophrenia, Huntington's disease, cognitive disorders and Parkinson’s disease. Mounting evidence suggests that this important signaling pathway is constructively regulated by the dopamine receptors (DRs). Thus, making members of this membrane protein family highly promising therapeutic targets as supported by both pre-clinical and clinical studies. Although some agonists of receptors in the human DR (hDR) family members (e.g. for dopamine D1-like receptors) are being intensively studied for therapeutic intervention, their success has been greatly hampered due to poor adherence and efficacy, or due to associated side effects. Relatedly, the polypharmacology of dopamine D1-like receptor and other hDRs have been discovered in recent studies. New knowledge based on structures of D1-like receptors (D1R and D5R) will not only reveal their signaling mechanisms, but also provide new understanding that can be exploited to facilitate rational drug design. hDRs belong to the G protein-coupled receptor (GPCR) family which is notorious for difficulties in generating diffraction-quality crystals that are essential for the determination of high-resolution structures by X-ray crystallography. This R&D proposal aims to develop a comprehensive and robust platform for structural and functional studies of dopamine D1-like receptors and complexes of hDRs with G proteins, for screening high- affinity nanobodies, antibodies, and ligands targeting these receptors. This platform will involve multiple steps that are closely interconnected and looped through a forward and backward feedback system. The PI has now also established strong collaborations with other research groups with different expertise as alternative approaches, including X-ray free electron laser, Microcrystal Electron Diffraction technique, etc. Three specific aims are proposed: (1) Structure/function studies of human D1R (hD1R) in the inactive state, (2) Using X-ray crystallography and computational biology approaches to study the putative active state of hD1R, and (3) Establishing optimized approaches for determining the structure of complexes of hD1R with G protein partners using EM imaging. The significance of this study is multi-fold on dopamine signaling pathway and related drug discovery studies: 1) we will gain insights into dopamine D1-like receptor functionalities and allosteric modulations, 2) we will be able to screen extensively to identify new high-affinity ligands for hDRs, 3) characterize the mechanisms of DR signaling and ligand selection between different dopamine receptor subfamilies, 4) stimulate hDR structure-based drug design, 5) examine hDRs/G protein complex signaling and reveal the activation mechanism, and 6) pave the road for the application of cryoEM technology on difficult membrane protein targets in the future.
摘要

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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Wei Liu其他文献

Porous TiC–TiB2–NiAl composites and effect of NiAl contents on pore structure and microstructure
多孔TiC—TiB2—NiAl复合材料及NiAl含量对孔结构和显微结构的影响
  • DOI:
    10.1179/1743290115y.0000000007
  • 发表时间:
    2015-06
  • 期刊:
  • 影响因子:
    1.4
  • 作者:
    Hongzhi Cui;Xiaojie Song;Wei Liu;Nan Hou
  • 通讯作者:
    Nan Hou

Wei Liu的其他文献

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{{ truncateString('Wei Liu', 18)}}的其他基金

New Strategies for Copper-Catalyzed Cross-Coupling of Alkyl Electrophiles
铜催化烷基亲电试剂交叉偶联的新策略
  • 批准号:
    10650863
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Structural Biology of Dopamine Signaling
多巴胺信号传导的结构生物学
  • 批准号:
    10543124
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Structural Biology of Dopamine Signaling
多巴胺信号传导的结构生物学
  • 批准号:
    10570686
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Real time biofeedback Tai Chi training for knee osteoarthritis: A feasibility study
实时生物反馈太极拳训练治疗膝骨关节炎:可行性研究
  • 批准号:
    10374319
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Real time biofeedback Tai Chi training for knee osteoarthritis: A feasibility study
实时生物反馈太极拳训练治疗膝骨关节炎:可行性研究
  • 批准号:
    9976459
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Real time biofeedback Tai Chi training for knee osteoarthritis: A feasibility study
实时生物反馈太极拳训练治疗膝骨关节炎:可行性研究
  • 批准号:
    10468265
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Real time biofeedback Tai Chi training for knee osteoarthritis: A feasibility study
实时生物反馈太极拳训练治疗膝骨关节炎:可行性研究
  • 批准号:
    9761465
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Structure and Function of Dopamine Receptors
多巴胺受体的结构和功能
  • 批准号:
    9317762
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
4D Robust Optimization in Intensity-Modulated Proton Therapy
调强质子治疗中的 4D 鲁棒优化
  • 批准号:
    8725494
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
4D Robust Optimization in Intensity-Modulated Proton Therapy
调强质子治疗中的 4D 鲁棒优化
  • 批准号:
    8353825
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:

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