DYNAMICS AND THERMODYNAMICS OF HUMAN CYTOMEGALOVIRUS PROTEINASE

人巨细胞病毒蛋白酶的动力学和热力学

• 批准号: 7598776
• 负责人: A PERCZEL
• 金额: $ 1.28万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7598776
• 关键词: Acquired Immunodeficiency Syndrome; Active Sites; Binding; Capsid; Complex; Computer Retrieval of Information on Scientific Projects Database; Cytomegalovirus; Data; Development; Disease; Endopeptidases; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Funding; Grant; Herpesviridae; Human; Individual; Infection; Institution; Life; Methods; Motion Pictures; Patients; Peptide Hydrolases; Positioning Attribute; Process; Proteins; Range; Research; Research Personnel; Resources; Simplexvirus; Source; Therapeutic Intervention; Thermodynamics; Triad Acrylic Resin; United States National Institutes of Health; Viral; inhibitor/antagonist; insight; novel; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human herpesviruses are responsible for a wide range of diseases. Human cytomegalovirus (HCMV) may cause life-threatening infections especially for immunecompromised individuals (e.g. AIDS patients). HCMV encodes a protease necessary for the assembly of the viral capsid. Therefore, this enzyme is an ideal candidate for therapeutic intervention. The binding of inhibitors to the HCMV proteinase causes large conformational changes in the protein. In a complex process characterized as an induced-fit mechanism, conformational changes near the active site appear to be important in forming substrate binding pockets and perhaps in positioning the active site triad His-His-Ser. To get insight into this process, we propose to use NMR advanced spectroscopic methods to study the dynamics of the active site region in both the free protein and in the enzyme-inhibitor complex. These experiments will allow us to provide a detailed picture of the motions involved in the mechanism of induced-fit. We also propose to determine the pKa values of the active site residues in order to decipher the catalytic mechanism in this novel catalytic triad at atomic level. These data will provide valuable information towards the understanding of the mechanism of action of this enzyme and subsequent development of potent inhibitors of HCMV proteinase.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 人类疱疹病毒是导致多种疾病的原因。人巨细胞病毒（HCMV）可能会导致危及生命的感染，特别是对免疫功能低下的个体（如艾滋病患者）。HCMV编码病毒衣壳组装所必需的蛋白酶。因此，这种酶是治疗干预的理想候选物。抑制剂与HCMV蛋白酶的结合引起蛋白质的大的构象变化。在一个复杂的过程中，其特征在于作为一个诱导的配合机制，附近的活性位点的构象变化似乎是重要的，在形成底物结合口袋，也许在定位的活性位点三联体His-His-Ser。为了深入了解这个过程中，我们建议使用NMR先进的光谱方法来研究的活性位点区域的动态中的游离蛋白质和酶抑制剂复合物。这些实验将使我们能够提供一个详细的图片的运动所涉及的机制诱导配合。我们还建议确定的活性位点残基的pKa值，以破译在这种新的催化三联体在原子水平上的催化机制。这些数据将提供有价值的信息，对这种酶的作用机制的理解和随后的发展，有效的抑制剂的HCMV蛋白酶。