Structural basis of Keap1 interactions with Nrf2.
Structural basis of Keap1 interactions with Nrf2.
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DOI：
10.1016/j.freeradbiomed.2015.05.034
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发表时间：
2015-11
影响因子：
7.4
通讯作者：
Bullock AN
中科院分区：
文献类型：
--
作者：
Canning P;Sorrell FJ;Bullock AN
Keap 1是BTB-Kelch家族的一个高度氧化还原敏感的成员，它与Cul 3蛋白组装形成Cullin-RING E3连接酶复合物，用于降解Nrf 2。氧化应激使Keap 1失效，使Nrf 2蛋白水平积累，用于关键应激反应基因的反式激活。因此，Keap 1-Nrf 2系统被广泛用于蛋白质-蛋白质相互作用抑制剂的开发，该抑制剂将稳定Nrf 2以在神经变性、炎症和癌症的条件下产生治疗效果。本文综述了Keap 1及其与Cul 3、Nrf 2底物和小分子拮抗剂的蛋白复合物的结构测定研究进展。现有的结构一起建立了一个合理的三维模型来解释Nrf 2的两个位点的结合，以及其有效的泛素化。Keap 1和Nrf 2是决定抗氧化反应的多结构域蛋白。结构模型表明Keap 1如何组装成Cullin-RING连接酶。二聚体Keap 1支持Nrf 2泛素化的两位点拴系机制。晶体结构揭示了Keap 1化学抑制剂的作用机制。
Keap1 is a highly redox-sensitive member of the BTB-Kelch family that assembles with the Cul3 protein to form a Cullin–RING E3 ligase complex for the degradation of Nrf2. Oxidative stress disables Keap1, allowing Nrf2 protein levels to accumulate for the transactivation of critical stress response genes. Consequently, the Keap1–Nrf2 system is extensively pursued for the development of protein–protein interaction inhibitors that will stabilize Nrf2 for therapeutic effect in conditions of neurodegeneration, inflammation, and cancer. Here we review current progress toward the structure determination of Keap1 and its protein complexes with Cul3, Nrf2 substrate, and small-molecule antagonists. Together the available structures establish a rational three-dimensional model to explain the two-site binding of Nrf2 as well as its efficient ubiquitination. Keap1 and Nrf2 are multidomain proteins that determine the antioxidant response. Structural models suggest how Keap1 assembles into a Cullin–RING ligase. Dimeric Keap1 supports a two-site tethering mechanism for Nrf2 ubiquitination. Crystal structures reveal the mechanism of action of chemical inhibitors of Keap1.