Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15

• Published in: Nature chemical biology Vol. 16; no. 1; pp. 7 - 14
• Main Authors: Faust, Tyler B., Yoon, Hojong, Nowak, Radosław P., Donovan, Katherine A., Li, Zhengnian, Cai, Quan, Eleuteri, Nicholas A., Zhang, Tinghu, Gray, Nathanael S., Fischer, Eric S.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2020; Nature Publishing Group
• Subjects: 631/154; 631/45/535; 631/535/1266; 631/92/613; Amino Acid Motifs; Animals; Aromatic compounds; BASIC BIOLOGICAL SCIENCES; Benzamides - chemistry; Benzamides - pharmacology; Biochemical Engineering; Biochemistry; Biology; Bioorganic Chemistry; Cancer; Cell Biology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Complementarity; Cryoelectron Microscopy; Crystal structure; Cullin; Cytotoxicity; drug discovery; Drugs; Fluorescence Resonance Energy Transfer; Humans; Indoles - chemistry; Indoles - pharmacology; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - metabolism; Kinetics; Ligands; Mutation; Proteasomes; Protein Binding; Protein Domains; Protein Interaction Mapping; Protein Structure, Secondary; Proteins; Proteolysis - drug effects; RNA Recognition Motif Proteins - chemistry; RNA Recognition Motif Proteins - metabolism; RNA-Binding Proteins; small moleculesp; Splicing; Splicing factors; Spodoptera; Structural analysis; structural biology; Substrates; Sulfonamides; Sulfonamides - chemistry; Sulfonamides - pharmacology; Ubiquitin-Protein Ligases - chemistry; X-ray crystallography; Xenopus
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/s41589-019-0378-3

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. Cryo-EM and crystal structural analysis of DDB1–DCAF15–DDA1 in complex with E7820 and RBM39 reveal that aryl-sulfonamides reshape the surface of the cullin RING ligase substrate receptor DCAF15 to bind and degrade the splicing factor RBM39.