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. Epub 2019 Nov 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Cryoelectron Microscopy
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Indoles / chemistry*
  • Indoles / pharmacology
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kinetics
  • Protein Binding
  • Protein Domains
  • Protein Interaction Mapping
  • Protein Structure, Secondary
  • Proteolysis / drug effects*
  • RNA Recognition Motif Proteins / chemistry*
  • RNA Recognition Motif Proteins / metabolism
  • RNA-Binding Proteins
  • Spodoptera
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology
  • Ubiquitin-Protein Ligases / chemistry
  • Xenopus

Substances

  • Benzamides
  • DCAF15 protein, human
  • HCC1 autoantigen
  • Indoles
  • Intracellular Signaling Peptides and Proteins
  • N-((5-bromo-2-thienyl)sulfonyl)-2,4-dichlorobenzamide
  • N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide
  • RBM23 protein, human
  • RNA Recognition Motif Proteins
  • RNA-Binding Proteins
  • Sulfonamides
  • N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzene-sulfonamide
  • Ubiquitin-Protein Ligases
  • CRL4 protein, human