Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15
Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15
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DOI：
10.1038/s41589-019-0378-3
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发表时间：
2020-01-01
影响因子：
14.8
通讯作者：
Fischer, Eric S.
中科院分区：
文献类型：
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作者：
Faust, Tyler B.;Yoon, Hojong;Fischer, Eric S.
研究药物E7820、indisulam和tasisulam（芳基磺酰胺类）以蛋白酶体依赖性机制促进剪接因子RBM 39的降解。虽然活性关键取决于cullin RING连接酶底物受体DCAF 15，但分子细节仍然难以捉摸。在这里，我们以4.4埃的分辨率展示了与RBM 39和E7820结合的DDB 1-DCAF 15-DDA 1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。我们发现，DCAF 15采用了一个新的折叠稳定的DDA 1，广泛的蛋白质-蛋白质之间的连接酶和基板的接触减轻低亲和力之间的相互作用芳基磺酰胺和DCAF 15。我们的数据证明了芳基磺酰胺如何新功能化DCAF 15上的浅的非保守口袋，以选择性地结合和降解RBM 39和密切相关的剪接因子RBM 23，而不需要高亲和力配体，这对分子胶降解剂的从头发现具有广泛的意义。
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 angstrom, 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.