The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically depends on the cullin RING ligase substrate receptor DCAF15, the molecular details remain elusive. Here we present the cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase complex bound to RBM39 and E7820 at a resolution of 4.4 Å, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a new fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrate how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high-affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.

译文

:研究用药物E7820,靛蓝和tasisulam(芳基磺酰胺类)以蛋白酶体依赖性机制促进剪接因子RBM39的降解。尽管活性主要取决于cullin RING连接酶底物受体DCAF15,但分子的细节仍然难以捉摸。在这里,我们介绍了DBM1-DCAF15-DDA1核心连接酶复合物以BM4.4的分辨率与RBM39和E7820结合的低温电磁结构,以及工程化的复合物的晶体结构。我们显示,DCAF15采用DDA1稳定的新折叠,并且连接酶和底物之间广泛的蛋白质接触减少了芳基磺酰胺与DCAF15之间的低亲和力相互作用。我们的数据表明,芳基磺酰胺如何在DCAF15上新功能化一个浅的,非保守的口袋,以选择性结合并降解RBM39和紧密相关的剪接因子RBM23,而无需高亲和力配体,这对从头开始具有广泛的意义。分子胶降解剂的发现。

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