Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15

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.

doi:10.1038/s41589-019-0378-3

Title: Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15

Journal Article · Mon Nov 04 00:00:00 EST 2019 · Nature Chemical Biology

DOI:https://doi.org/10.1038/s41589-019-0378-3· OSTI ID:1581823

Faust, Tyler B. ^[1];

^[1];

^[1]; Li, Zhengnian ^[1]; Cai, Quan ^[1]; Eleuteri, Nicholas A. ^[1]; Zhang, Tinghu ^[1];

^[1];

^[1]

Dana–Farber Cancer Inst., Boston, MA (United States); Harvard Medical School, Boston, MA (United States)

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. Here, 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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); Damon Runyon Cancer Research Foundation; NIH NIGMS; NIH-ORIP HEI

Grant/Contract Number:: AC02-06CH11357; NCI R01CA214608; 1F32CA232772-01; DRR-50–18; P41 GM103403; S10 RR029205

OSTI ID:: 1581823

Journal Information:: Nature Chemical Biology, Vol. 16, Issue 1; ISSN 1552-4450

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 83 works

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Title: Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15

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