Journal: Nature Communications

Article Title: A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation

doi: 10.1038/s41467-025-65094-3

Figure Lengend Snippet: a Chemical structure of MRT-31619, OUN20985 (CRBN homo-PROTAC) and Lenalidomide. b , c Global quantitative proteomics in Jurkat cells. Volcano plots show compound/DMSO protein abundance upon treatment with 1 μM of MRT-31619 or CRBN homo-PROTAC for 1 h, 3 h and 24 h, and with 10 μM of MRT-31619 or CRBN homo-PROTAC for 24 h. d HEK293T_HiBiT-CRBN cells were treated with MRT-31619 for 1 h. Bortezomib at 2 μM, MLN4924 at 2 μM, and lenalidomide at 20 μM were added 1 h prior to MRT-31619 treatment. Values were normalized to DMSO treatment. Four biological replicates were plotted as mean ± Standard Deviation (SD). e HEK293T_HiBiT-CRBN cells were treated with CRBN homo-PROTAC for 1 h. Bortezomib at 2 μM, MLN4924 at 2 μM, and lenalidomide at 20 μM were added 1 h prior to CRBN homo-PROTAC treatment. Values were normalized to DMSO treatment. Four biological replicates were plotted as mean ± SD. f NanoBRET assay for HaloTag-CRBN and CRBN-NanoLuc constructs upon MRT-31619 or lenalidomide treatment. In the double treatment condition, lenalidomide was added at 20 μM, 1 h prior to MRT-31619 treatment. Values were normalized to DMSO treatment. Three biological replicates were plotted as mean ± Standard Error of Measurement (SEM). g NanoBRET assay for HaloTag-CRBN and CRBN-NanoLuc (CRBN-Nluc) wild-type (WT) and W386A constructs upon MRT-31619 treatment. Values were normalized to DMSO treatment. Three biological replicates were plotted as mean ± SEM. Source data are provided as a Source Data file.

Article Snippet: Cells were treated for 3 h with DMSO (Sigma Cat#41639) at 0.1% final concentration, MRT compounds or lenalidomide (Selleckchem Cat#S1029) at serial dilution using a Tecan D300e Digital Dispenser.

Techniques: Quantitative Proteomics, Standard Deviation, Construct

Journal: Nature Communications

Article Title: A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation

doi: 10.1038/s41467-025-65094-3

Figure Lengend Snippet: a The cis CRBN (CRBN 1 ) binds one MRT-31619 molecule (MGD 1 ) at the tri-tryptophan pocket and interacts with the trans MRT-31619 molecule (MGD 2 ) via a hydrogen bond to W400. b CRBN W400 interacts with the CK1α G-loop via a hydrogen bond in the presence of lenalidomide. c Superposition of panels a and b indicates that MGD 2 is a structural mimic of the CK1α G-loop and employs the same hydrogen bond. d – f Chemical structures of MRT-31619, MRT-31015, or MRT-30568 and their corresponding global quantitative proteomics data in Jurkat cells. Volcano plots show compound/DMSO protein abundance upon treatment with 10 μM of MRT-31619, MRT-31015, or MRT-30568 for 24 h. g HEK293T_HiBiT-CRBN degradation upon MRT-31619, MRT-31015, or MRT-30568 treatment for 1 h. Four biological replicates were plotted as mean ± SD. h NanoBRET assay for HaloTag-CRBN and CRBN-NanoLuc constructs upon MRT-31619, MRT-31015, or MRT-30568 treatment. Three biological replicates were plotted as mean ± SEM. i Flow-induced dispersion analysis (FIDA) for MRT-31619, MRT-31015, or MRT-30568 and the corresponding EC 50 and Max R h values. The predicted value of R h calculated from the cryo-EM structure of the ternary complex is 7.47 nm. Three biological replicates were plotted as mean ± SD. Source data are provided as a Source Data file.

Article Snippet: Cells were treated for 3 h with DMSO (Sigma Cat#41639) at 0.1% final concentration, MRT compounds or lenalidomide (Selleckchem Cat#S1029) at serial dilution using a Tecan D300e Digital Dispenser.

Techniques: Quantitative Proteomics, Construct, Dispersion, Cryo-EM Sample Prep