STRUCTURE OF AN E3 LIGASE COMPLEX

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 蛋白质泛素化是一种广泛应用于真核生物调控的翻译后修饰。泛素最广为人知的功能是标记蛋白酶体降解的蛋白质。这一功能和其他功能需要首先由E1酶激活泛素，然后与~40个E2结合物中的一个结合。最后，泛素化的特异性是由E3连接酶赋予的。大多数E3的活性是由一个环状结构域决定的，它与E2~泛素结合物结合，激活泛素的释放，攻击底物蛋白中的赖氨酸残基，与E3中的一个单独结构域结合。超过600个人类基因编码E3，与这些酶在控制许多细胞过程中的已知功能以及它们参与多种疾病的功能一致。 解决这个E3复合体的结构将有助于理解其功能，并有助于从总体上理解E3的作用机制。我们对E3功能的基本原理了解得越详细，我们就越能准确地理解它们是如何调节的，以及疾病突变对活动有什么影响。最后但并非最不重要的一点是，通过了解E3的作用机制，我们应该能够设计针对E3的小分子抑制剂，并解释此类药物的效果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. 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. 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.