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Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15


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.

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Fig. 1: Cryo-EM structure of the DDB1∆B–DCAF15–DDA1 complex bound to E7820 and RBM39RRM2.
Fig. 2: Crystal structure of the DDB1∆B–DCAF15split–DDA1–E7820–RBM39RRM2 complex.
Fig. 3: DDA1 stabilizes the CRL4DCAF15 complex and facilitates RBM39 recruitment.
Fig. 4: Aryl-sulfonamide binding to DCAF15.
Fig. 5: Interprotein contacts between DCAF15 and RBM39.
Fig. 6: Topological and evolutionary constraints on E7820 activity.

Data availability

Structural coordinates for DDB1∆B–DDA1–DCAF15–E7820–RBM39, DDB1∆B–DDA1–DCAF15–tasisulam–RBM39 and DDB1∆B–DDA1–DCAF15–indisulam–RBM39 have been deposited in the PDB under accession numbers 6Q0R, 6Q0V and 6Q0W. The cryo-EM volume data are available at the Electron Microscopy Data Bank under accession numbers EMD-20554 and EMD-20553. MS raw data files have been deposited in the Proteomics Identifications archive under accession number PXD014536. Other data and materials are available from the authors upon reasonable request.


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We acknowledge H.-S. Seo for help with ITC experiments. Cryo-EM data were collected at the UMass cryo-EM facility, with help from K. Song and C. Xu. Financial support for this work was provided by NIH grant NCI R01CA214608 (to E.S.F.) and an F32 fellowship 1F32CA232772-01 (to T.F.). E.S.F. is a Damon Runyon-Rachleff Innovator supported in part by the Damon Runyon Cancer Research Foundation (DRR-50–18). This work is based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by NIH NIGMS (P41 GM103403) and NIH-ORIP HEI grant (S10 RR029205). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated by Argonne National Laboratory under contract number DE-AC02-06CH11357. This research was, in part, supported by the National Cancer Institute’s National cryo-EM facility at the Frederick National Laboratory for Cancer Research.

Author information




T.B.F., H.Y., N.S.G., R.P.N. and E.S.F. initiated the project and designed experiments; T.B.F., H.Y. and R.P.N. conducted protein purification; T.B.F. performed crystallization and cryo-EM experiments; H.Y. developed and performed biochemical assays; R.P.N., T.B.F. and E.S.F. collected and processed X-ray diffraction data; N.A.E. and K.A.D. performed the MS experiments; H.Y., Z.L. and Q.C. synthesized small molecules with input from T.Z; N.S.G. and E.S.F. supervised the project; and T.B.F., H.Y. and E.S.F. wrote the manuscript with input from all authors.

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Correspondence to Eric S. Fischer.

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Competing interests

E.S.F. is a founder and/or member of the scientific advisory board (SAB) and equity holder of C4 Therapeutics and Civetta Therapeutics, and a consultant to Novartis, AbbVie and Pfizer. The Fischer laboratory receives research funding from Novartis, Deerfield and Astellas. N.S.G. is a founder, scientific advisory board member and equity holder in Gatekeeper, Syros, Petra, C4, B2S and Soltego. The Gray laboratory receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Her2llc, Deerfield and Sanofi. N.S.G., E.S.F, H.Y., Q.C., T.Z., T.F., R.P.N and K.A.D. are inventors on patent applications (PCT/US2018/065701 and PCT/US2019/014919) submitted by the Dana-Farber Cancer Institute.

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Faust, T.B., Yoon, H., Nowak, R.P. et al. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat Chem Biol 16, 7–14 (2020).

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