Proteomics

Dataset Information

0

Biotinylated MMH2 pulldown LCMS

ABSTRACT: Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism. We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4-DCAF16 ligase to the second bromodomain of BRD4. To gain a deeper understanding into the potential off-target effects of more reactive degraders, we conducted streptavidin pulldowns of K562 lysate incubated with engineered MMH2-Biotin, a probe molecule that appends linker-biotin onto the second exit vector of MMH2.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

SUBMITTER: Anna Schmoker  

LAB HEAD: Eric Fischer

PROVIDER: PXD051457 | Pride | 2025-05-06

REPOSITORIES: Pride

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Dataset's files

Source:
Action DRS
esf5_0038.mgf Mgf
esf5_0038.raw Raw
esf5_0039.mgf Mgf
esf5_0039.raw Raw
esf5_0040.mgf Mgf
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Publications

Template-assisted covalent modification underlies activity of covalent molecular glues.

Li Yen-Der YD   Ma Michelle W MW   Hassan Muhammad Murtaza MM   Hunkeler Moritz M   Teng Mingxing M   Puvar Kedar K   Rutter Justine C JC   Lumpkin Ryan J RJ   Sandoval Brittany B   Jin Cyrus Y CY   Schmoker Anna M AM   Ficarro Scott B SB   Cheong Hakyung H   Metivier Rebecca J RJ   Wang Michelle Y MY   Xu Shawn S   Byun Woong Sub WS   Groendyke Brian J BJ   You Inchul I   Sigua Logan H LH   Tavares Isidoro I   Zou Charles C   Tsai Jonathan M JM   Park Paul M C PMC   Yoon Hojong H   Majewski Felix C FC   Sperling Haniya T HT   Marto Jarrod A JA   Qi Jun J   Nowak Radosław P RP   Donovan Katherine A KA   Słabicki Mikołaj M   Gray Nathanael S NS   Fischer Eric S ES   Ebert Benjamin L BL  

Nature chemical biology 20240729 12

Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans-labeling covalent molecular glue mechanism, termed 'template-assisted covalent modification'. We identified a new series of BRD4 molecular glue degraders that recruit CUL4<sup>DCAF16</sup> ligase to the se  ...[more]

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