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Structure paper

TitleStructural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15.
Journal, issue, pagesNat Chem Biol, Vol. 16, Issue 1, Page 7-14, Year 2020
Publish dateNov 4, 2019
AuthorsTyler B Faust / Hojong Yoon / Radosław P Nowak / Katherine A Donovan / Zhengnian Li / Quan Cai / Nicholas A Eleuteri / Tinghu Zhang / Nathanael S Gray / Eric S Fischer /
PubMed AbstractThe 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 ...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.
External linksNat Chem Biol / PubMed:31686031 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.9 - 10.0 Å
Structure data

EMDB-20553:
Cryo-EM structure of DDB1dB-DCAF15-DDA1 bound to E7820 and RBM39
Method: EM (single particle) / Resolution: 4.4 Å

EMDB-20554:
Cryo-EM structure of DDB1-DCAF15 bound to E7820 and the second RRM of RBM39
Method: EM (single particle) / Resolution: 10.0 Å

PDB-6q0r:
Structure of DDB1-DDA1-DCAF15 complex bound to E7820 and RBM39
Method: X-RAY DIFFRACTION / Resolution: 2.9 Å

PDB-6q0v:
Structure of DDB1-DDA1-DCAF15 complex bound to tasisulam and RBM39
Method: X-RAY DIFFRACTION / Resolution: 2.9 Å

PDB-6q0w:
Structure of DDB1-DDA1-DCAF15 complex bound to Indisulam and RBM39
Method: X-RAY DIFFRACTION / Resolution: 2.9 Å

Chemicals

ChemComp-OXM:
OXAMIC ACID

ChemComp-O6M:
3-cyano-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-P7M:
N-[(5-bromothiophen-2-yl)sulfonyl]-2,4-dichlorobenzamide

ChemComp-EF6:
N~1~-(3-chloro-1H-indol-7-yl)benzene-1,4-disulfonamide / antitumor, inhibitor, medication*YM

Source
  • homo sapiens (human)
KeywordsLIGASE / Ubiquitin / homeostasis / targeted protein degradation

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