CYP17A1 STRUCTURE FUNCTION, CRITICAL ENZYME IN HUMAN ANDROGEN BIOSYNTHESIS

CYP17A1 结构功能，人类雄激素生物合成中的关键酶

• 批准号: 8359666
• 负责人: Emily E Scott
• 金额: $ 6.78万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359666
• 关键词: Adrenal Glands; Anabolism; Androgens; Blood Circulation; Cancer Etiology; Cessation of life; Clinical Trials; Crystallization; Cytochrome P450; Engineering; Enzymes; Funding; Grant; Human; Left; Ligand Binding; Ligands; Link; Malignant neoplasm of prostate; National Center for Research Resources; Outcome; Pregnenolone; Principal Investigator; Production; Prostate; Research; Research Infrastructure; Resources; Second Primary Cancers; Source; Steroids; Structure; Tissues; United States; United States National Institutes of Health; Work; cost; deprivation; improved; inhibitor/antagonist; men; prevent; protein structure function

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Prostate cancer is the most common occurring cancer and the second-leading cause of cancer-related death for men in the United States. Progression is strongly linked to the presence of androgens. Traditional androgen deprivation therapy significantly decreases androgen production in prostate tissue, but fails to inhibit adrenal androgen synthesis, leaving a basal level of androgens in circulation. Cytochrome P450 17A1 (CYP17A1) is responsible for the conversion of pregnenolone to androgens in both tissues. Thus, inhibition of CYP17A1 provides a strategy for complete deprivation of androgens in the treatment of prostate cancer. Several CYP17A1 inhibitors are currently in clinical trials, but there is currently no structural information about CYP17A1. The lack of a CYP17A1 crystal structure prevents an understanding of how current inhibitors work and how they might be improved. The objective of this proposal is to determine a structure of CYP17A1. Understanding the interaction between CYP17A1 and its ligands would provide information about how this enzyme functions. Our central hypothesis is that a crystal structure of CYP17A1 will reveal specific interactions that correspond to unique features of the enzyme. The specific aims are: 1) to engineer a soluble version of CYP17A1, 2) to optimize expression and purification strategies to generate mg quantities of pure, stable, functionally active, monodisperse CYP17A1 suitable for crystallization efforts, and 3) to grow diffraction-quality crystals of CYP17A1. The expected outcome of the proposed study is the first crystal structure of the important steroid biosynthetic enzyme CYP17A1. This structure will enable a detailed understanding of ligand binding modes.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 前列腺癌是最常见的癌症，也是美国男性癌症相关死亡的第二大原因。进展与雄激素的存在密切相关。传统的雄激素剥夺疗法显着减少前列腺组织中雄激素的产生，但无法抑制肾上腺雄激素的合成，从而使循环中的雄激素保持在基础水平。细胞色素 P450 17A1 (CYP17A1) 负责在两种组织中将孕烯醇酮转化为雄激素。因此，CYP17A1的抑制提供了在前列腺癌的治疗中完全剥夺雄激素的策略。目前有几种CYP17A1抑制剂正在进行临床试验，但目前还没有有关CYP17A1的结构信息。由于缺乏 CYP17A1 晶体结构，我们无法了解现有抑制剂的工作原理以及如何改进它们。该提案的目的是确定 CYP17A1 的结构。 了解 CYP17A1 及其配体之间的相互作用将提供有关该酶如何发挥作用的信息。 我们的中心假设是 CYP17A1 的晶体结构将揭示与酶的独特特征相对应的特定相互作用。具体目标是：1) 设计可溶版本的 CYP17A1，2) 优化表达和纯化策略，以产生毫克量的纯、稳定、功能活性、单分散的 CYP17A1，适合结晶工作，以及 3) 提高衍射质量CYP17A1 晶体。该研究的预期结果是重要的类固醇生物合成酶 CYP17A1 的第一个晶体结构。该结构将使人们能够详细了解配体结合模式。