PXD040570

PXD040570 is an original dataset announced via ProteomeXchange.

Title	BRD4 degradation via stabilization of a native interaction with DCAF16
Description	Targeted protein degradation is a modality based on small molecules that induce proximity between a protein of interest (POI) and an E3 ubiquitin ligase, thus prompting POI ubiquitination and degradation. To expand the reach of TPD, current research is geared to unlock novel E3s. To that end, the transcriptional co-activator protein BRD4 has emerged as a frequently used POI. Derivatization of known BRD4 ligands with structurally diverse substituents has yielded a suite of potent BRD4 degraders, thus generating the notion that BRD4 is particularly amenable to TPD. Here, we mechanistically characterize two BRD4 degraders via orthogonal CRISPR screens. Despite their structural dissimilarity, both degraders functionally converge on a unifying mechanism of action that involves the CRL4DCAF16 ligase complex. Using recombinant reconstitution, as well as biophysical and structural elucidation, we demonstrate that BRD4 has an intrinsic activity for DCAF16, which is further enhanced by both compounds. We uncover a novel mode of molecular recognition based on multivalent "gluing" of BRD4 onto DCAF16 that requires both bromodomains of BRD4. Our data thus imply a substantial conceptual overlap between PROTACs and molecular glue degraders, and highlight multivalency as a novel concept in the design of proximity-inducing drugs.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:19:38.649.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD040570
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Andrea Rukavina
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-03-03 05:34:13	ID requested
1	2024-01-08 05:33:06	announced
2	2024-03-18 07:28:52	announced	2024-03-18: Updated project metadata.
⏵ 3	2024-10-22 06:19:39	announced	2024-10-22: Updated project metadata.

10.6019/PXD040570;

Hsia O, Hinterndorfer M, Cowan AD, Iso K, Ishida T, Sundaramoorthy R, Nakasone MA, Imrichova H, Sch, ä, tz C, Rukavina A, Husnjak K, Wegner M, Correa-S, á, ez A, Craigon C, Casement R, Maniaci C, Testa A, Kaulich M, Dikic I, Winter GE, Ciulli A, Targeted protein degradation via intramolecular bivalent glues. Nature, 627(8002):204-211(2024) [pubmed]

10.1038/s41586-024-07089-6;

submitter keyword: BRD4 degradation,KBM7, small molecule induced proximity, chemical proteomics, GNE-0011, PROTAC, Orbitrap Fusion Lumos, LC-MS/MS

Georg Winter
contact affiliation	Dr Georg E. Winter, Winter Lab, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
contact email	gwinter@cemm.oeaw.ac.at
lab head
Andrea Rukavina
contact affiliation	The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
contact email	arukavina@cemm.oeaw.ac.at
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD040570
     1. Label: PRIDE project
     2. Name: BRD4 degradation via stabilization of a native interaction with DCAF16