Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15.,Nature Chemical Biology

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Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15.
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2019-11-04 , DOI: 10.1038/s41589-019-0378-3
Tyler B Faust _{1,

2} , Hojong Yoon _{1,

2} , Radosław P Nowak _{1,

2} , Katherine A Donovan _{1,

2} , Zhengnian Li _{1,

2} , Quan Cai _{1,

2} , Nicholas A Eleuteri _{1,

2} , Tinghu Zhang _{1,

2} , Nathanael S Gray _{1,

2} , Eric S Fischer _{1,

2}

Affiliation

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.

中文翻译：

结构互补性促进 E7820 介导的 DCAF15 对 RBM39 的降解。

研究药物 E7820、indisulam 和 tasisulam（芳基磺胺类药物）以蛋白酶体依赖性机制促进剪接因子 RBM39 的降解。虽然活性严重依赖于 cullin RING 连接酶底物受体 DCAF15，但分子细节仍然难以捉摸。在这里，我们以 4.4 Å 的分辨率展示了与 RBM39 和 E7820 结合的 DDB1-DCAF15-DDA1 核心连接酶复合物的冷冻电镜结构，以及工程亚复合物的晶体结构。我们表明 DCAF15 采用了由 DDA1 稳定的新折叠，并且连接酶和底物之间广泛的蛋白质 - 蛋白质接触减轻了芳基磺酰胺和 DCAF15 之间的低亲和力相互作用。我们的数据证明了芳基磺胺类药物是如何对浅层进行新功能化的，

更新日期：2019-11-04

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