英国邓迪大学Alessio Ciulli等研究人员合作通过分子内二价胶定向降解蛋白质。相关论文于2024年2月21日在线发表于国际学术期刊《自然》。

研究人员利用正交遗传筛选、生物物理表征和结构重组，研究了BRD2和BRD4的双功能降解剂（称为分子内二价胶，IBG）的作用机制，发现它们不像蛋白水解-靶向嵌合体（PROTAC）那样反式连接靶标和连接酶，而是同时顺式接合和连接靶标蛋白的两个相邻结构域。这种构象变化将BRD4与E3连接酶DCAF11或DCAF16“粘合”在一起，利用了目标连接酶的内在亲和力，而这种亲和力在没有化合物的情况下不会转化为BRD4的降解。

对BRD4-IBG1-DCAF16三元复合物结构的深入研究指导研究人员合理设计了低皮摩尔效力的改良降解剂。因此，研究人员引入了一种靶向蛋白质降解的新模式，它通过顺式桥接蛋白质结构域来增强与E3连接酶的表面互补性，从而实现有效的泛素化和降解。

据介绍，靶向蛋白降解是一种药理学模式，它基于诱导E3泛素连接酶和靶蛋白接近，以促进靶蛋白泛素化和蛋白酶体降解。实现这一目标的途径有两种：一种是PROTAC——由两个独立分子组成的双功能化合物，可分别结合靶蛋白和E3连接酶；另一种是分子胶，可单价结合连接酶或靶蛋白。

附：英文原文

Title: Targeted protein degradation via intramolecular bivalent glues

Author: Hsia, Oliver, Hinterndorfer, Matthias, Cowan, Angus D., Iso, Kentaro, Ishida, Tasuku, Sundaramoorthy, Ramasubramanian, Nakasone, Mark A., Imrichova, Hana, Schtz, Caroline, Rukavina, Andrea, Husnjak, Koraljka, Wegner, Martin, Correa-Sez, Alejandro, Craigon, Conner, Casement, Ryan, Maniaci, Chiara, Testa, Andrea, Kaulich, Manuel, Dikic, Ivan, Winter, Georg E., Ciulli, Alessio

Issue&Volume: 2024-02-21

Abstract: Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)—bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target1,2,3,4. Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change ‘glues’ BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target–ligase affinities that do not translate to BRD4 degradation in the absence of compound. Structural insights into the ternary BRD4–IBG1–DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.

DOI: 10.1038/s41586-024-07089-6

Source: https://www.nature.com/articles/s41586-024-07089-6