STRUCTURE OF AN E3 LIGASE COMPLEX

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。 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。泛素最为人所知的功能是标记蛋白酶体降解的蛋白质。这种功能和其他功能需要首先通过E1酶激活泛素，然后结合到约40种E2缀合物中的一种。最后，泛素化的特异性由E3连接酶赋予。大多数E3的活性由RING结构域指定，RING结构域结合至E2-泛素缀合物并激活泛素的释放以攻击底物蛋白中的赖氨酸残基，所述底物蛋白结合至E3中的单独结构域。超过600个人类基因编码E3，这与这些酶在控制许多细胞过程中的已知功能一致，并且与多种疾病有关。 解决E3复合物的结构将有助于理解其功能，并有助于理解E3的一般作用机制。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被调节的，以及疾病突变对活性的影响。最后但并非最不重要的是，通过了解E3的作用机制，我们应该能够设计靶向E3的小分子抑制剂并解释这些药物的作用。

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.