STRUCTURE OF AN E3 LIGASE COMPLEX

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 蛋白质泛素化是一种广泛应用于真核生物的翻译后修饰 监管。泛素最为人所知的功能是标记蛋白酶体的蛋白质 退化。这一功能和其他功能需要首先由E1酶激活泛素， 然后结合到~40个E_2共轭气体中的一个。最后，泛素化的特异性是 由E3连接酶授予。大多数E3的活动由环域指定，该环域绑定 与E2~泛素结合物结合，并激活泛素的释放以攻击体内的赖氨酸残基 一种底物蛋白，与E3中的单独结构域结合。超过600个人类基因编码 E3S，与这些酶在许多细胞控制中的已知功能一致 过程，以及与多种疾病的关系。 解决这个E3复合体的结构将有助于理解它的功能和应该 有助于从总体上理解E3的作用机制。越多 详细了解E3功能背后的基本原理，我们就会更 准确地说，我们将能够了解它们是如何被调节的，以及它们对疾病的影响 突变对活性有影响。最后但并非最不重要的一点是，通过了解作用机制 对于E3，我们应该能够设计E3靶向的小分子抑制剂，并解释 这类药物的效果。

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.