哈佛大学Christina M. Woo团队的一项最新研究开发出E3连接酶适配器cereblon上的变构位点鉴定。2026年1月21日，国际知名学术期刊《自然》发表了这一成果。

在这里，研究团队报道了一个进化上保守的CRBN上的隐变构结合位点。小分子SB-405483结合变构位点，协同增强正构配体的结合，改变其新底物降解谱。对100多种正构配体及其降解靶标的调查揭示了SB-405483增强或抑制降解结果的化合物和新底物类别的趋势。结构研究通过改变CRBNopen的构象分布到新的CRBNint和增加CRBNclosed状态，为变构配体的作用提供了机制基础。CRBN上一个改变正构配体功能效应的隐变构结合位点的发现，为提高CRBN治疗药物的选择性和疗效开辟了新的方向，具有广泛的意义。

据了解，小脑（CRBN）是沙利度胺衍生物的靶点，通过招募新底物降解，对某些血液病肿瘤达到治疗效果。尽管对正位沙利度胺衍生物进行了深入的研究，但对CRBN上的其他结合位点知之甚少。

附：英文原文

Title: Identification of an allosteric site on the E3 ligase adapter cereblon

Author: Dippon, Vanessa N., Rizvi, Zeba, Choudhry, Anthony E., Chung, Chun-wa, Alkuraya, Ibrahim F., Xu, Wenqing, Tao, Xavier B., Jurewicz, Anthony J., Schneck, Jessica L., Chen, Wenqian, Curnutt, Nicole M., Kabir, Farah, Chan, Kwok-Ho, Queisser, Markus A., Musetti, Caterina, Dai, Han, Lander, Gabriel C., Benowitz, Andrew B., Woo, Christina M.

Issue&Volume: 2026-01-21

Abstract: Cereblon (CRBN) is the target of thalidomide derivatives1 that achieve therapeutic efficacy against some haematologic neoplasias2,3,4 by recruiting neosubstrates for degradation5,6,7. Despite the intense investigation of orthosteric thalidomide derivatives, little is known about alternate binding sites on CRBN. Here we report an evolutionarily conserved cryptic allosteric binding site on CRBN. Small-molecule SB-405483 binds the allosteric site to cooperatively enhance the binding of orthosteric ligands and alter their neosubstrate degradation profiles. A survey of over 100 orthosteric ligands and their degradation targets reveals trends in the classes of compounds and neosubstrates in which degradation outcomes are enhanced or inhibited by SB-405483. Structural investigations provide a mechanistic basis for the effects of the allosteric ligand by shifting the conformational distribution of CRBNopen to a novel CRBNint and increasing the CRBNclosed state. The discovery of a cryptic allosteric binding site on CRBN that alters the functional effects of orthosteric ligands opens new directions with broad implications for improving the selectivity and efficacy of CRBN therapeutics.

DOI: 10.1038/s41586-025-09994-w

Source: https://www.nature.com/articles/s41586-025-09994-w