PXD014536 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Structural complementarity offsets low receptor affinity in E7820-mediated RBM39 degradation by CRL4DCAF15 |
Description | 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. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_04:03:41.455.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Eric Fischer |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2019-07-09 06:11:17 | ID requested | |
1 | 2019-07-10 00:37:55 | announced | |
⏵ 2 | 2024-10-22 04:03:41 | announced | 2024-10-22: Updated project metadata. |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: DCAF15, E7820, crl4, sulfonamide, ubiquitin, cullin, RBM39 |
Contact List
Eric Fischer |
contact affiliation | Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA |
contact email | eric_fischer@dfci.harvard.edu |
lab head | |
Eric Fischer |
contact affiliation | Dana-Farber Cancer Institute |
contact email | eric_fischer@dfci.harvard.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD014536
- Label: PRIDE project
- Name: Structural complementarity offsets low receptor affinity in E7820-mediated RBM39 degradation by CRL4DCAF15