PT - JOURNAL ARTICLE AU - Tyler Faust AU - Hojong Yoon AU - Radosław P. Nowak AU - Katherine A. Donovan AU - Zhengnian Li AU - Quan Cai AU - Nicholas A. Eleuteri AU - Tinghu Zhang AU - Nathanael S. Gray AU - Eric S. Fischer TI - Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15 AID - 10.1101/738534 DP - 2019 Jan 01 TA - bioRxiv PG - 738534 4099 - http://biorxiv.org/content/early/2019/08/16/738534.short 4100 - http://biorxiv.org/content/early/2019/08/16/738534.full AB - 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 4.4 Å resolution, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a novel 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 demonstrates 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.