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Structural complementarity offsets low receptor affinity in E7820-mediated RBM39 degradation by CRL4DCAF15

ABSTRACT: The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome and CRL4DCAF15 ubiquitin ligase-dependent mechanism, however the molecular details of this activity remain elusive. Here we present the cryo-EM structure of DDB1-DCAF15-DDA1 bound to RBM39 and E7820 at 4.4 Å resolution, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a novel fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate the low affinity interaction between aryl-sulfonamides and DCAF15. Our data demonstrates how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and RBM23 without the requirement for a high affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Neuroblastoma

SUBMITTER: Eric Fischer

LAB HEAD: Eric Fischer

PROVIDER: PXD014536 | Pride | 2019-07-10

REPOSITORIES: Pride

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			Action	DRS
	esf_2010.raw	Raw
	esf_2011.raw	Raw
	esf_2012.raw	Raw
	esf_2013.raw	Raw
	esf_2014.raw	Raw

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