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Nat Chem Biol January 1, 2020; 16 (1): 7-14.

Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15.

Faust TB , Yoon H , Nowak RP , Donovan KA , Li Z , Cai Q , Eleuteri NA , Zhang T , Gray NS , Fischer ES .

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 ID: 31686031
PMC ID: PMC6917914
Article link: Nat Chem Biol
Grant support: [+]

Species referenced: Xenopus
Genes referenced: ddb1 rbx1

Article Images: [+] show captions
References [+] :
Abdulrahman, A set of baculovirus transfer vectors for screening of affinity tags and parallel expression strategies. 2009, Pubmed