Journal
NATURE CHEMICAL BIOLOGY
Volume 16, Issue 1, Pages 7-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-019-0378-3
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Funding
- NIH [NCI R01CA214608, 1F32CA232772-01]
- Damon Runyon Cancer Research Foundation [DRR-50-18]
- NIH NIGMS [P41 GM103403]
- NIH-ORIP HEI grant [S10 RR029205]
- Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility [DE-AC02-06CH11357]
- National Cancer Institute's National cryo-EM facility at the Frederick National Laboratory for Cancer Research
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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.
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