STRUCTURAL STUDIES OF G PROTEIN-COUPLED RECEPTORS

G蛋白偶联受体的结构研究

基本信息

  • 批准号:
    7426436
  • 负责人:
  • 金额:
    $ 19.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-06-01 至 2011-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): G protein-coupled receptors (GPCRs) are important in biomedicine because they are the targets of about 50% of commercially available drugs. Only little is known about the structure and function of these receptors in any molecular or atomic detail. The only three-dimensional X-ray crystallographic model for a GPCR is that of ground-state rhodopsin in an inactive conformation. Rhodopsin, the light-sensing protein in retina, has been extensively studied as a prototypical GPCR. The integral membrane protein contains seven trans- membrane helices that provide a binding site for its 11-cis-retinal chromophore. Absorption of a photon triggers a change in the chromophore's conformation and then in the receptor's tertiary structure. This results in alterations on the receptor's cytoplasmic surface that permit binding of transducin (Gt), its cognate G- protein. This initiates further steps in the signal transduction process. Most GPCRs respond to molecular signals in the form of ligands. Binding of specific ligands by specific GPCRs results in a ligand-specific cellular response. The ligand binding site for most GPCRs coincides with the retinal pocket in rhodopsin. Binding of a ligand causes the same kinds of conformational changes as does absorption of a photon in rhodopsin, and the remaining molecular mechanisms for signal transduction are similar for all GPCRs. Our understanding of GPCR structure and function will be increased by components of this proposal. First, the oligomeric state of activated GPCRS will be addressed by experiments probing the quaternary structure of rhodopsin isolated under varying detergent condtions. Assessment of physiological function will be made for these preparations. The second part of the project will use single-molecule force microscopy to probe the interactions between the membrane and rhodopsin or the serotonin 5HT1AR receptor to understand the dynamics and stabilities of GPCRs. Crystallographic studies of activated rhodopsin make up the third part of the project. The last component of the project calls for further efforts in purifying the transducin/rhodopsin complex for biochemical and structural characterization. These projects all provide structural information for an important class of proteins, a class that provides extensive experimental and theoretical challenges. The importance of the protein family for human health makes this effort worthwhile.
描述(申请人提供):G蛋白偶联受体(GPCRs)在生物医学中很重要,因为它们是大约50%的商业可用药物的靶标。关于这些受体的任何分子或原子细节的结构和功能,人们知之甚少。GPCR的唯一三维X射线结晶学模型是基态视紫红质的非活性构象。视紫红质是视网膜中的一种感光蛋白,作为一种典型的GPCR已被广泛研究。完整的膜蛋白含有7个跨膜螺旋,为其11顺式视网膜发色团提供了一个结合部位。吸收一个光子会引起发色团构象的改变,进而改变受体的三级结构。这导致受体的细胞质表面发生变化,允许与其同源G蛋白转导蛋白(GT)结合。这启动了信号转导过程中的进一步步骤。大多数GPCR以配体的形式对分子信号做出反应。特定的GPCRs与特定的配体结合会导致特定的配体特异性细胞反应。大多数GPCRs的配体结合部位与视紫红质中的视网膜袋相吻合。配体的结合引起的构象变化与光在视紫红质中的吸收引起的构象变化相同,其余的信号转导分子机制对于所有GPCRs都是相似的。通过本提案的组成部分,我们将加深对GPCR结构和功能的理解。首先,将通过实验探索在不同洗涤剂条件下分离的视紫红质的四级结构来解决激活的GPCRs的低聚状态。将对这些准备工作进行生理功能评估。该项目的第二部分将使用单分子作用力显微镜来探索膜与视紫红质或5-羟色胺5HT1AR受体之间的相互作用,以了解GPCRs的动力学和稳定性。激活视紫红质的结晶学研究是该项目的第三部分。该项目的最后一个组成部分要求进一步努力提纯转导蛋白/视紫红质复合体,以进行生化和结构表征。这些项目都提供了一类重要蛋白质的结构信息,这类蛋白质提供了广泛的实验和理论挑战。蛋白质家族对人类健康的重要性使得这一努力是值得的。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Krzysztof Palczewski其他文献

Krzysztof Palczewski的其他文献

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{{ truncateString('Krzysztof Palczewski', 18)}}的其他基金

Precision genome editing in vivo to treat retinal diseases
体内精准基因组编辑治疗视网膜疾病
  • 批准号:
    10565189
  • 财政年份:
    2023
  • 资助金额:
    $ 19.01万
  • 项目类别:
Visual Sciences Training Program (VSTP)
视觉科学培训计划(VSTP)
  • 批准号:
    10410300
  • 财政年份:
    2022
  • 资助金额:
    $ 19.01万
  • 项目类别:
Visual Sciences Training Program (VSTP)
视觉科学培训计划(VSTP)
  • 批准号:
    10615907
  • 财政年份:
    2022
  • 资助金额:
    $ 19.01万
  • 项目类别:
The complex role of phosphodiesterase 6 in rod photoreceptor health and function
磷酸二酯酶 6 在视杆光感受器健康和功能中的复杂作用
  • 批准号:
    10662478
  • 财政年份:
    2020
  • 资助金额:
    $ 19.01万
  • 项目类别:
The complex role of phosphodiesterase 6 in rod photoreceptor health and function
磷酸二酯酶 6 在视杆光感受器健康和功能中的复杂作用
  • 批准号:
    10455528
  • 财政年份:
    2020
  • 资助金额:
    $ 19.01万
  • 项目类别:
Visual Sciences Training Program
视觉科学培训计划
  • 批准号:
    9280013
  • 财政年份:
    2017
  • 资助金额:
    $ 19.01万
  • 项目类别:
Use of systems pharmacology to prevent rod and cone photoreceptor degeneration
利用系统药理学预防视杆细胞和视锥细胞光感受器变性
  • 批准号:
    9554184
  • 财政年份:
    2017
  • 资助金额:
    $ 19.01万
  • 项目类别:
A two-photon ophthalmoscope for human retinal imaging and functional testing
用于人类视网膜成像和功能测试的双光子检眼镜
  • 批准号:
    9059094
  • 财政年份:
    2015
  • 资助金额:
    $ 19.01万
  • 项目类别:
Regulation of Retinal Physiology by micro-RNAs
micro-RNA 对视网膜生理学的调节
  • 批准号:
    8627170
  • 财政年份:
    2013
  • 资助金额:
    $ 19.01万
  • 项目类别:
Regulation of Retinal Physiology by micro-RNAs
micro-RNA 对视网膜生理学的调节
  • 批准号:
    8431587
  • 财政年份:
    2013
  • 资助金额:
    $ 19.01万
  • 项目类别:

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  • 批准号:
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  • 财政年份:
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