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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

基本信息

批准号：
10615088
负责人：
John C Hackett
金额：
$ 33.56万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615088
关键词：
Address Adopted Adverse effects Architecture Aromatase Binding Binding Proteins Binding Sites Catalysis Clinic Complement Complex Cytochrome P450 Cytochrome a Data Deuterium Disease Drug Interactions Electron Transport Endocrine System Diseases Environment Enzymes Equilibrium Estrogens Estrone Family Gynecologic Heme Human Hybrids Hydrogen Infertility Investigation Kinetics Ligand Binding Ligands Lipid Bilayers Lipids Malignant Neoplasms Maps Mass Spectrum Analysis Membrane Methods Modeling Neutrons Oxidation-Reduction Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phylogenetic Analysis Physiological Population Positioning Attribute Property Protein Conformation Protein Dynamics Proteins Public Health Research Resources Roentgen Rays Role Sampling Structure Surface Testing Tissues Trees Variant Xenobiotics anastrozole androgen biosynthesis conformational conversion drug development flexibility hormone biosynthesis inhibitor insight malignant endocrine gland neoplasm molecular dynamics nanodisk novel novel strategies preference steroid hormone biosynthesis tool

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 (CYP) 负责一系列令人眼花缭乱的转化。异生素和激素的生物合成。超过70%的药物是通过CYP代谢的；因此巨大的资源专门用于药物开发中底物和抑制剂的鉴定，以避免后期消耗，或引入诊所后不良药物相互作用。其中，CYPs参与类固醇激素生物合成是内分泌疾病药物治疗的关键靶点之一癌症。 CYP 的催化选择性范围和转化底物的广度是巨大的；然而，用于实现这种灵活性的蛋白质动力学、配体结合和催化的相互作用仍然存在不太了解。在这个空白中，我们不知道这些物质是如何受到其生理影响的。语境。我们采用了人类芳香酶（CYP19A1），负责雌激素的生物合成雄激素作为解决这些长期存在的重要问题的模型。系统发育分析支持 CYP19A1 是最原始的人类 CYP 之一，它在功能上代表了那些催化连续转化的类固醇生成酶。 CYP19A1 的翻译相关性不能被低估了，因为它在维持许多组织方面发挥着至关重要的作用，并且已被证明具有巨大的作用作为妇科疾病、癌症和不孕症药物治疗靶点的价值。具体有以下三个为了检验我们的假设，我们将：1) 绘制 19A1 配体进入、产物流出的路径图，并描绘出选择性的结构基础。工作假设是 i) 底物、中间产物、和抑制剂产生独特的平衡动力学，并且 ii) 选择性是由瞬时结合赋予的当配体通过不同的通道进入和离开酶时状态。 2) 描绘膜的影响 19A1 催化、配体结合动力学和全局动力学的复杂性。工作假设是 i) 选择性主要由涉及多种蛋白质状态和构象转变的动力学决定，ii) 催化和抑制性 19A1 复合物表现出不同的动力学，以及 iii) 蛋白质动力学和结合动力学受膜特性的影响。 3) 确定 19A1-ND 在可变环境中的架构小角度 X 射线和中子散射。工作假设是插入深度和方向 19A1 由双层的表面和本体特性决定。这些目标在技术上是—— 独立但收敛的方法，组合起来高度协同，不仅允许对 CYP19A1 的新颖见解，同时也揭示了将改变我们对 CYP 功能理解的范式。