Dynamics and Interactions of Cytochrome P450 19A1

细胞色素 P450 19A1 的动力学和相互作用

基本信息

  • 批准号:
    10541020
  • 负责人:
  • 金额:
    $ 25.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-01 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

The cytochromes P450 (CYPs) are responsible for a dazzling array of transformations in the disposition of xenobiotics and biosyntheses of hormones. Over 70% of drugs are metabolized by CYPs; hence tremendous resources are devoted to identification of substrates and inhibitors in drug development to avoid later attrition, or adverse drug interactions following introduction into the clinic. Among these, CYPs involved in steroid hormone biosyntheses are among the key targets for the pharmacotherapy of endocrine disorders and cancers. The range of catalytic selectivity and the breadth of substrates transformed by CYPs are immense; however the interplay of protein dynamics, ligand binding, and catalysis used to achieve this flexibility remains poorly understood. Within this void, nothing is known about how these are impacted by their physiological context. We have adopted human aromatase (CYP19A1), responsible for estrogen biosynthesis from androgens, as a model to address these longstanding and important questions. Phylogenetic analysis supports that CYP19A1 is among the most primordial human CYPs and it is functionally representative of those steroidogenic enzymes catalyzing sequential transformations. The translational relevance of CYP19A1 cannot be underestimated since it has vital role in maintaining numerous tissues and has demonstrated immense value as a pharmacotherapy target for gynecological disorders, cancers and infertility. There are three Specific Aims to test our hypotheses, we will: 1) Map pathways for 19A1 ligand entry, product egress, and delineate the structural underpinnings of selectivity. The working hypotheses are that i) substrates, intermediate products, and inhibitors give rise to unique equilibrium dynamics and ii) that selectivity is conferred by transient bound states as ligands enter and exit the enzyme through distinct channels. 2) Delineate the impact of membrane complexity on catalysis, ligand binding kinetics and global dynamics in 19A1. The working hypotheses are i) Selectivity is dominated by kinetics involving multiple protein states and conformational transitions, ii) catalytic and inhibitory 19A1 complexes display distinct dynamics, and iii) both protein dynamics and binding kinetics are impacted by membrane properties. 3) Determine the architecture of 19A1-NDs in variable environments by small-angle x-ray and neutron scattering. The working hypothesis is that the insertion depth and orientation of 19A1 are determined by the surface and bulk properties of the bilayer. These Aims are technically- independent, but convergent approaches that are highly synergistic in combination, and will not only allow novel insight into CYP19A1, but also unveil paradigms that will transform our understanding of CYP function.
细胞色素P450 (CYPs)负责处理一系列令人眼花缭乱的转化

项目成果

期刊论文数量(0)
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John C Hackett其他文献

John C Hackett的其他文献

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{{ truncateString('John C Hackett', 18)}}的其他基金

Dynamics and Interactions of Cytochrome P450 19A1
细胞色素 P450 19A1 的动力学和相互作用
  • 批准号:
    10201672
  • 财政年份:
    2020
  • 资助金额:
    $ 25.97万
  • 项目类别:
Dynamics and Interactions of Cytochrome P450 19A1
细胞色素 P450 19A1 的动力学和相互作用
  • 批准号:
    10401431
  • 财政年份:
    2020
  • 资助金额:
    $ 25.97万
  • 项目类别:
Dynamics and Interactions of Cytochrome P450 19A1
细胞色素 P450 19A1 的动力学和相互作用
  • 批准号:
    10615088
  • 财政年份:
    2020
  • 资助金额:
    $ 25.97万
  • 项目类别:
Computational and Vibrational Probes of CYP3A4 Solution Dynamics
CYP3A4 溶液动力学的计算和振动探针
  • 批准号:
    8862610
  • 财政年份:
    2015
  • 资助金额:
    $ 25.97万
  • 项目类别:
Computational and Vibrational Probes of CYP3A4 Solution Dynamics
CYP3A4 溶液动力学的计算和振动探针
  • 批准号:
    9108970
  • 财政年份:
    2015
  • 资助金额:
    $ 25.97万
  • 项目类别:
Computational and Vibrational Probes of CYP3A4 Solution Dynamics
CYP3A4 溶液动力学的计算和振动探针
  • 批准号:
    9260902
  • 财政年份:
    2015
  • 资助金额:
    $ 25.97万
  • 项目类别:
Enzyme Environmental Effects in Complex Cytochrome P450-Catalyzed Reactions
复杂细胞色素 P450 催化反应中的酶环境影响
  • 批准号:
    8325771
  • 财政年份:
    2010
  • 资助金额:
    $ 25.97万
  • 项目类别:
Enzyme Environmental Effects in Complex Cytochrome P450-Catalyzed Reactions
复杂细胞色素 P450 催化反应中的酶环境影响
  • 批准号:
    8322837
  • 财政年份:
    2010
  • 资助金额:
    $ 25.97万
  • 项目类别:
Enzyme Environmental Effects in Complex Cytochrome P450-Catalyzed Reactions
复杂细胞色素 P450 催化反应中的酶环境影响
  • 批准号:
    8136486
  • 财政年份:
    2010
  • 资助金额:
    $ 25.97万
  • 项目类别:
Enzyme Environmental Effects in Complex Cytochrome P450-Catalyzed Reactions
复杂细胞色素 P450 催化反应中的酶环境影响
  • 批准号:
    7993455
  • 财政年份:
    2010
  • 资助金额:
    $ 25.97万
  • 项目类别:

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  • 财政年份:
    2022
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Inter-Enzyme Crosstalk in the Cytochrome P450 Ensemble: Implications for the Effects of Alcohol on Drug Metabolism and Alcohol-Drug Interactions
细胞色素 P450 整体中的酶间串扰:酒精对药物代谢和酒精-药物相互作用影响的影响
  • 批准号:
    10445619
  • 财政年份:
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Defining Structural and Functional Differences Between Cytochrome P450 11B1 and 11B2 Interactions with Redox Partner Adrenodoxin for Developing Cushing’s Disease and Primary Aldosteronism Treatments
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  • 项目类别:
Dynamics and Interactions of Cytochrome P450 19A1
细胞色素 P450 19A1 的动力学和相互作用
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    10201672
  • 财政年份:
    2020
  • 资助金额:
    $ 25.97万
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Dynamics and Interactions of Cytochrome P450 19A1
细胞色素 P450 19A1 的动力学和相互作用
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    10401431
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    2020
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    $ 25.97万
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Dynamics and Interactions of Cytochrome P450 19A1
细胞色素 P450 19A1 的动力学和相互作用
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    10615088
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    2020
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    $ 25.97万
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