Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15

  • Nat Chem Biol. 2020 Jan;16(1):7-14. doi: 10.1038/s41589-019-0378-3.
Tyler B Faust  #  1  2 ,  Hojong Yoon  #  1  2 ,  Radosław P Nowak  1  2 ,  Katherine A Donovan  1  2 ,  Zhengnian Li  1  2 ,  Quan Cai  1  2 ,  Nicholas A Eleuteri  1  2 ,  Tinghu Zhang  1  2 ,  Nathanael S Gray  1  2 ,  Eric S Fischer  3  4
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 31686031 DOI: 10.1038/s41589-019-0378-3
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 a resolution of 4.4 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.

Products