6Q0R

Structure of DDB1-DDA1-DCAF15 complex bound to E7820 and RBM39

Summary for 6Q0R

• Entry DOI: 10.2210/pdb6q0r/pdb
• Descriptor: DNA damage-binding protein 1, DDB1- and CUL4-associated factor 15, RNA-binding protein 39, ... (9 entities in total)
• Functional Keywords: ubiquitin, homeostasis, targeted protein degradation, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 185025.71

Authors

Faust, T.,Yoon, H.,Nowak, R.P.,Donovan, K.A.,Li, Z.,Cai, Q.,Eleuteri, N.A.,Zhang, T.,Gray, N.S.,Fischer, E.S. (deposition date: 2019-08-02, release date: 2019-11-13, Last modification date: 2023-10-11)

Primary citation

Faust, T.B.,Yoon, H.,Nowak, R.P.,Donovan, K.A.,Li, Z.,Cai, Q.,Eleuteri, N.A.,Zhang, T.,Gray, N.S.,Fischer, E.S.
Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15.
Nat.Chem.Biol., 16:7-14, 2020

PubMed 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.

PubMed: 31686031
DOI: 10.1038/s41589-019-0378-3

Experimental method

X-RAY DIFFRACTION (2.9 Å)