Structure and Dynamics of Cyclooxygenase Catalysis and Inhibition

环加氧酶催化和抑制的结构和动力学

基本信息

项目摘要

 DESCRIPTION (provided by applicant): Cyclooxygenases (COX-1 and COX-2) oxygenate arachidonic acid to generate prostaglandins and are inhibited by aspirin, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and COX-2 selective diarylheterocyclic based drugs (coxibs). COX-1 and COX-2 are membrane-associated homodimers that bind to one leaflet of the lipid bilayer via a membrane-binding domain comprised of amphipathic helices. As a consequence, the enzymes have traditionally required the presence of detergents to maintain the protein in a stable and active form during functional and structural characterization. A new paradigm has emerged with respect to COX catalysis and regulation. In this model, COX functions as a conformational heterodimer with one monomer active at a given time. Common dietary FAs and nonselective NSAIDs bind to one monomer of the homodimer to modulate the oxygenation of substrates in the other monomer through an allosteric/catalytic couple. The molecular mechanism governing crosstalk between monomers is not known and static pictures derived from crystal structures of COX do not provide any insight into the conformational motions responsible for this dynamical interplay. We surmise that detergent binding and the restricted confines of the crystal lattice have masked these conformational motions. Hence, a new approach to study COX catalysis in solution and in the absence of detergent is needed. We propose to couple the use of nanodisc-reconstituted COX-2 with site- directed spin-labeling ESR spectroscopic technologies to characterize the protein conformational dynamics associated with COX catalysis and inhibition. The objectives are to identify the conformational motions responsible for: a) ligand access to the cyclooxygenase channel and b) communication between monomers. Understanding the molecular basis of how the binding of different ligands induces conformational motions responsible for crosstalk between monomers bridges the gap between the static information derived from COX crystal structure analysis and the dynamical character of COX as it relates to the modulation of COX function.
 性状(由申请方提供):环氧化酶(考克斯-1和考克斯-2)可通过花生四烯酸生成异甘草定,并可被阿司匹林、非选择性非甾体抗炎药(NSAID)和考克斯-2选择性二芳基杂环类药物(昔布类)抑制。考克斯-1和考克斯-2是膜相关的同源二聚体,通过由两亲性螺旋组成的膜结合结构域与脂质双层的一个小叶结合。因此,酶传统上需要去污剂的存在以在功能和结构表征期间保持蛋白质处于稳定和活性形式。关于考克斯催化和调节已经出现了新的范例。在这个模型中,考克斯作为一个构象异源二聚体的功能与一个单体活性在给定的时间。常见的膳食脂肪酸和非选择性非甾体抗炎药结合到同二聚体的一个单体,通过变构/催化偶来调节另一个单体中底物的氧合。控制单体之间串扰的分子机制尚不清楚,并且来自考克斯晶体结构的静态图片不能提供对这种动态相互作用的构象运动的任何洞察。我们推测,洗涤剂的结合和晶格的局限性掩盖了这些构象运动。因此,需要一种新的方法来研究考克斯催化在溶液中和在没有洗涤剂的情况下。我们建议将纳米盘重构的考克斯-2与定点自旋标记ESR光谱技术结合使用,以表征与考克斯催化和抑制相关的蛋白质构象动力学。目的是确定负责以下的构象运动:a)配体进入环加氧酶通道和B)单体之间的通信。了解不同配体的结合如何诱导导致单体之间串扰的构象运动的分子基础,弥合了源自考克斯晶体结构分析的静态信息与考克斯的动力学特征之间的差距,因为它涉及考克斯功能的调节。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

MICHAEL G MALKOWSKI其他文献

MICHAEL G MALKOWSKI的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('MICHAEL G MALKOWSKI', 18)}}的其他基金

Structure and Dynamics of Cyclooxygenase Catalysis and Inhibition
环加氧酶催化和抑制的结构和动力学
  • 批准号:
    9275693
  • 财政年份:
    2015
  • 资助金额:
    $ 38.32万
  • 项目类别:
Structure and Dynamics of Cyclooxygenase Catalysis and Inhibition
环加氧酶催化和抑制的结构和动力学
  • 批准号:
    9315899
  • 财政年份:
    2015
  • 资助金额:
    $ 38.32万
  • 项目类别:
STRUCTURAL BIOLOGY OF MEMBRANE PROTEINS
膜蛋白的结构生物学
  • 批准号:
    8363518
  • 财政年份:
    2011
  • 资助金额:
    $ 38.32万
  • 项目类别:
HAUPTMAN-WOODWARD STRUCTURAL GENOMICS
豪普特曼-伍德沃德结构基因组学
  • 批准号:
    8362086
  • 财政年份:
    2011
  • 资助金额:
    $ 38.32万
  • 项目类别:
STRUCTURAL BIOLOGY OF MEMBRANE PROTEINS
膜蛋白的结构生物学
  • 批准号:
    8171494
  • 财政年份:
    2010
  • 资助金额:
    $ 38.32万
  • 项目类别:
Multi-level optimization of membrane proteins for crystallography
用于晶体学的膜蛋白的多级优化
  • 批准号:
    8152512
  • 财政年份:
    2010
  • 资助金额:
    $ 38.32万
  • 项目类别:
HAUPTMAN-WOODWARD STRUCTURAL GENOMICS
豪普特曼-伍德沃德结构基因组学
  • 批准号:
    8169987
  • 财政年份:
    2010
  • 资助金额:
    $ 38.32万
  • 项目类别:
HAUPTMAN-WOODWARD STRUCTURAL GENOMICS
豪普特曼-伍德沃德结构基因组学
  • 批准号:
    7954272
  • 财政年份:
    2009
  • 资助金额:
    $ 38.32万
  • 项目类别:
STRUCTURAL BIOLOGY OF MEMBRANE PROTEINS
膜蛋白的结构生物学
  • 批准号:
    7955553
  • 财政年份:
    2009
  • 资助金额:
    $ 38.32万
  • 项目类别:
Structural Biology of Oxylipin Biosynthesis
氧脂质生物合成的结构生物学
  • 批准号:
    7924306
  • 财政年份:
    2009
  • 资助金额:
    $ 38.32万
  • 项目类别:

相似海外基金

Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
  • 批准号:
    MR/Y009568/1
  • 财政年份:
    2024
  • 资助金额:
    $ 38.32万
  • 项目类别:
    Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
  • 批准号:
    10090332
  • 财政年份:
    2024
  • 资助金额:
    $ 38.32万
  • 项目类别:
    Collaborative R&D
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
  • 批准号:
    MR/X02329X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 38.32万
  • 项目类别:
    Fellowship
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
  • 批准号:
    MR/X021882/1
  • 财政年份:
    2024
  • 资助金额:
    $ 38.32万
  • 项目类别:
    Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
  • 批准号:
    MR/X029557/1
  • 财政年份:
    2024
  • 资助金额:
    $ 38.32万
  • 项目类别:
    Research Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
    EP/Y003527/1
  • 财政年份:
    2024
  • 资助金额:
    $ 38.32万
  • 项目类别:
    Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
  • 批准号:
    EP/Y030338/1
  • 财政年份:
    2024
  • 资助金额:
    $ 38.32万
  • 项目类别:
    Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
  • 批准号:
    2312694
  • 财政年份:
    2024
  • 资助金额:
    $ 38.32万
  • 项目类别:
    Standard Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
  • 批准号:
    24K19395
  • 财政年份:
    2024
  • 资助金额:
    $ 38.32万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Acute human gingivitis systems biology
人类急性牙龈炎系统生物学
  • 批准号:
    484000
  • 财政年份:
    2023
  • 资助金额:
    $ 38.32万
  • 项目类别:
    Operating Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了