2. Academic Validation
  3. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15

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

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.

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