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bioRxiv · 10.1101/738534

Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15

Faust, T.·Yoon, H.·Nowak, R. P.·Donovan, K. A.·Li, Z.·Cai, Q.·Eleuteri, N. A.·Zhang, T.·Gray, N. S.·Fischer, E. S.
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Abstract

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 [A] 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.

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Faust, T., Yoon, H., Nowak, R. P., Donovan, K. A., Li, Z., Cai, Q., Eleuteri, N. A., Zhang, T., Gray, N. S., Fischer, E. S.. 2019-08-16. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. https://doi.org/10.1101/738534

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