研究人员表示，cereblon（CRBN）是一种泛素连接酶（E3）底物受体蛋白，被CRBN E3连接酶调节药物（CELMoD）药剂联合使用，这些药物针对治疗相关的蛋白质进行降解。之前的晶体学研究确定了CRBN的沙利度胺结合域（TBD）内的药物结合位点，但药物诱导新底物结合的变构反应仍不清楚。
研究人员对DNA损伤结合蛋白1（DDB1）-CRBN apo复合物进行了冷冻电镜分析，并将这些结构与单独存在CELMoD化合物和与新底物复合物的DDB1-CRBN进行比较。CELMoD化合物与TBD的结合对于触发CRBN从开放构象到典型的封闭构象的重排是必要和充分的。新底物Ikaros只与闭合的CRBN构象稳定地结合，说明了异构作用对CELMoD化合物疗效的重要性，并为提高疗效的结构指导设计策略提供了依据。
附：英文原文
Title: Molecular glue CELMoD compounds are regulators of cereblon conformation
Author: Edmond R. Watson, Scott Novick, Mary E. Matyskiela, Philip P. Chamberlain, Andres H. de la Pea, Jinyi Zhu, Eileen Tran, Patrick R. Griffin, Ingrid E. Wertz, Gabriel C. Lander
Issue&Volume: 2022-11-04
Abstract: Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN’s thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo–electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)–CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy.
DOI: add7574
Source: https://www.science.org/doi/10.1126/science.add7574