Complex Structures of Human MDM2 with Interacting Proteins Reveal the Regulation Mechanism of p53

Abstract

Human MDM2 (murine double minute 2), amplified and overexpressed frequently in most of tumors and cancers, directly interacts with and inhibits the tumor suppressor protein p53. Understanding the regulation mechanism of MDM2 has recently been highlighted because of its roles in the regulation of p53 in cancer biology. MDM2 contains three domains. The N–terminal region interacts with p53 and downregulates its activity. The RING finger domain has ubiquitin ligase activity that can mediate p53 ubiquitination and degradation. Many studies showed that the central region of MDM2 is critical for p53 activation and tumor suppression. To date, more than twenty proteins have been shown to bind to this central region and further to be involved in the regulations of p53. However, how these interacting proteins precisely interact with MDM2 remains to be elucidated. We solved the first structure of the human MDM2–RPL11 complex. Both the acidic domain and C4 zinc finger of MDM2 are essential for RPL11 binding. Moreover, another unexpectedly zinc finger that forms inter-molecularly within the complex. A small molecule imidazole was found to be chelated in this zinc finger, which might be a promising start of drug design. These structural and functional information combining with earlier studies of MDM2 with other interacting proteins establish MDM2 as a novel class of therapeutic targets in human diseases such as cancers, yield insights into the MDM2–p53 surveillance pathway and could also yield useful anticancer strategies.