Reverter David, Wu Kenneth, Erdene Tudeviin Gan, Pan Zhen-Qiang, Wilkinson Keith D, Lima Christopher D
Structural Biology Program, Sloan-Kettering Institute, New York, NY 10021, USA.
J Mol Biol. 2005 Jan 7;345(1):141-51. doi: 10.1016/j.jmb.2004.10.022.
The Nedd8 conjugation pathway is conserved from yeast to humans and is essential in many organisms. Nedd8 is conjugated to cullin proteins in a process that alters SCF E3 ubiquitin ligase activity, and it is presumed that Nedd8 deconjugation would reverse these effects. We now report the X-ray structures of the human Nedd8-specific protease, Den1, in a complex with the inhibitor Nedd8 aldehyde, thus revealing a model for the tetrahedral transition state intermediate generated during proteolysis. Although Den1 is closely related to the SUMO-specific protease family (Ulp/Senp family), structural analysis of the interface suggests determinants involved in Nedd8 selectivity by Den1 over other ubiquitin-like family members and suggests how the Ulp/Senp architecture has been modified to interact with different ubiquitin-like modifiers.
Nedd8缀合途径从酵母到人类都保守，且在许多生物体中至关重要。Nedd8在一个改变SCF E3泛素连接酶活性的过程中与cullin蛋白缀合，据推测Nedd8去缀合会逆转这些效应。我们现在报告人Nedd8特异性蛋白酶Den1与抑制剂Nedd8醛形成复合物的X射线结构，从而揭示了蛋白水解过程中产生的四面体过渡态中间体的模型。尽管Den1与SUMO特异性蛋白酶家族（Ulp/Senp家族）密切相关，但对界面的结构分析表明了Den1对Nedd8的选择性高于其他泛素样家族成员所涉及的决定因素，并表明Ulp/Senp结构是如何被修饰以与不同的泛素样修饰剂相互作用的。
