Extended Data Fig. 5: Observed changes in BRISC subunit solvent accessibility and secondary structure in the presence of FX-171-C by HDX-MS.
From: Molecular glues that inhibit deubiquitylase activity and inflammatory signaling
a, Wood’s plots generated with Deuteros showing the differences in deuterium uptake over all four HDX timepoints from three technical replicates, comparing BRISC in the absence and presence of FX-171-C. Regions highlighted in grey indicate peptides with no significant change, calculated using a 99% confidence interval, between the two conditions. The dashed line indicates the 99% confidence limit. Peptides are coloured in red to indicate deprotection in the presence of inhibitor, and blue to indicate protection. b, Peptides mapped onto BRISC dimer structure, highlighting peptides near BLUE binding site and at the interface of two BRCC45 subunits. B36 = BRCC36; B45 = BRCC45. c, Example deuterium uptake curves in the absence and presence of FX-171-C. Data points are mean ± SEM from three technical replicates. d, BLUE compounds are allosteric inhibitors and do not disrupt the BRCC36 Zn2+ binding site. e, CSN5 active site in complex with inhibitor CSN5i-3 (PDB: 5J0G). f, Left, BRCC45 UEV-M bound to FX-171-C aligned to Ubc13 in complex with BAY 11-7082 (PDB: 4ONN) and NSC697923 (PDB: 4ONM). Right, BRCC45 UEV-M bound to FX-171-C aligned to Cdc34 in complex with CC0651 (PDB: 3RZ3).
