Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15.

Publication Type:

Journal Article


Nat Chem Biol, Volume 16, Issue 1, p.7-14 (2020)


<p>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&thinsp;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.</p>

Structural coordinates for DDB1∆B–DDA1–DCAF15–E7820–RBM39, DDB1∆B–DDA1–DCAF15–tasisulam–RBM39 and DDB1∆B–DDA1–DCAF15–indisulam–RBM39 have been deposited in the PDB under accession numbers 6Q0R, 6Q0V and 6Q0W.