PXD047138-1
PXD047138 is an original dataset announced via ProteomeXchange.
Dataset Summary
Title | Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders |
Description | Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics1-3. Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs4-6. The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism, which we term “template-assisted covalent modification”. We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). BRD4BD2, in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 Å cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4BD2 have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16Cys58 covalent modification. Systematic mutagenesis of both DCAF16 and BRD4BD2 revealed that the loop conformation around BRD4His437, rather than specific side chains, is critical for BD2 selectivity. Supporting a general applicability, we find that a subset of compounds leads to a drug-induced GAK-BRD4 interaction stabilized by covalent modification of GAK. Together our work establishes “template-assisted covalent modification” as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology. |
HostingRepository | PRIDE |
AnnounceDate | 2024-08-09 |
AnnouncementXML | Submission_2024-08-09_06:01:23.943.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 | iodoacetamide derivatized residue |
Instrument | timsTOF Pro 2 |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
---|---|---|---|
0 | 2023-11-21 13:42:41 | ID requested | |
⏵ 1 | 2024-08-09 06:01:24 | announced |
Publication List
10.1038/s41589-024-01668-4; |
Li YD, Ma MW, Hassan MM, Hunkeler M, Teng M, Puvar K, Rutter JC, Lumpkin RJ, Sandoval B, Jin CY, Schmoker AM, Ficarro SB, Cheong H, Metivier RJ, Wang MY, Xu S, Byun WS, Groendyke BJ, You I, Sigua LH, Tavares I, Zou C, Tsai JM, Park PMC, Yoon H, Majewski FC, Sperling HT, Marto JA, Qi J, Nowak RP, Donovan KA, S, ł, abicki M, Gray NS, Fischer ES, Ebert BL, Template-assisted covalent modification underlies activity of covalent molecular glues. Nat Chem Biol, ():(2024) [pubmed] |
Keyword List
submitter keyword: DCAF16, JQ1, Molecular glue, degrader, bromodomain, template-assisted |
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
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PRIDE project URI |
Repository Record List
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