STRUCTURE OF AN E3 LIGASE COMPLEX

E3 连接酶复合物的结构

• 批准号: 8362470
• 负责人: CLAUDIO A.P. JOAZEIRO
• 金额: $ 2.57万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362470
• 关键词: Binding; Cell physiology; Complex; Disease; Enzymes; Funding; Genes; Grant; Human; Lysine; Microscopy; Molecular; Mutation; National Center for Research Resources; Pharmaceutical Preparations; Post-Translational Protein Processing; Principal Investigator; Protein Binding; Proteins; Regulation; Research; Research Infrastructure; Resources; Source; Specific qualifier value; Specificity; Structure; Ubiquitin; Ubiquitination; United States National Institutes of Health; cost; design; gamma-Glutamyl Hydrolase; inhibitor/antagonist; small molecule; ubiquitin-protein ligase

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. Protein ubiquitination is a post-translational modification widely utilized in eukaryotic regulation. The best known function of ubiquitin is to mark proteins for proteasomal degradation. This and other functions require first activation of ubiquitin by the E1 enzyme, followed by binding to one of ~40 E2 conjugases. Finally, specificity of ubiquitination is conferred by E3 ligases. The activity of most E3s is specified by a RING domain, which binds to the E2~ubiquitin conjugate and activates release of ubiquitin to attack a lysine residue in a substrate protein, bound to a separate domain in the E3. Over 600 human genes encode E3s, consistent with these enzymes' known functions in the control of many cellular processes, and with their involvement in multiple diseases. Solving the structure of this E3 complex will help understand its function and should contribute to the understanding of the mechanism of action of E3s in general. The more detailed our understanding of basic principles underlying E3 function becomes, the more accurately we will be able to understand how they are regulated and what effects disease mutations have on activity. Last but not least, by understanding of the mechanism of action of E3s we should be able to design E3-targeting small molecule inhibitors and interpret the effects of such drugs.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 蛋白质泛素化是真核生物广泛应用的一种翻译后修饰 调控泛素最为人所知的功能是标记蛋白质中的蛋白酶体 降解这一功能和其他功能首先需要E1酶激活泛素， 随后结合至约40种E2缀合物中的一种。最后，泛素化的特异性是 由E3连接酶赋予。大多数E3的活性由RING结构域指定，其结合 与E2-泛素缀合物结合并激活泛素的释放以攻击E2-泛素缀合物中的赖氨酸残基。 一种底物蛋白，与E3中的一个独立结构域结合。超过600个人类基因编码 E3，与这些酶在控制许多细胞中的已知功能一致。 过程，并与他们参与多种疾病。 解决这个E3复合体的结构将有助于理解它的功能， 有助于理解E3的一般作用机制。越 我们对E3功能的基本原理的理解越详细， 我们将能够准确地了解它们是如何调节的，以及它们对疾病的影响。 突变具有活性。最后但并非最不重要的是，通过了解作用机制， 我们应该能够设计E3靶向的小分子抑制剂，并解释E3的作用。 这些药物的影响。