PXD014536

PXD014536 is an original dataset announced via ProteomeXchange.

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

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.

Dataset with its publication pending

submitter keyword: DCAF15, E7820, crl4, sulfonamide, ubiquitin, cullin, RBM39

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

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2019/07/PXD014536

PRIDE project URI

• PRIDE
  1. PXD014536
     1. Label: PRIDE project
     2. Name: Structural complementarity offsets low receptor affinity in E7820-mediated RBM39 degradation by CRL4DCAF15