Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide

摘要

1957年作为一种温和的镇静剂在欧洲推出的"沙立度胺",过去被广泛用来防止孕妇晨吐。这导致数以千计有多种缺陷的儿童出生,该药物也在1962年被撤出市场。自那时以来,"沙立度胺"及其衍生物成为癌症"多发性骨髓瘤"及与之相关的疾病"5q-发育异常"的有效治疗药物。"沙立度胺"的主要致畸目标是cereblon(CRBN),后者是E3泛素连接酶复合物CUL4-RBX1-DDB1-CRBN(CRL4~(CRBN))的构成部分。在这篇论文中,Nicolas ThomS及同事发表了与"沙立度胺"相结合以及与相关药物"来那度胺"和"泊马度胺"相结合的DDB1-CRBN E3泛素连接酶的晶体结构。该结构确立了决定CRBN的对映选择性作用的分子机制。进一步的结构一功能分析显示,这些药物具有双重功能：干扰某些细胞基质与E3连接酶的结合,但促进其他细胞基质的结合,从而调制细胞蛋白的降解。%In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4~(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4~(CRBN). Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4~(CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4~(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4~(CRBN) while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.