Ubiquitin Biology and Molecular Glues: Nuclear hormone receptors
Nuclear hormone receptors (NHRs) are versatile transcription factors, crucial for gene regulation through ligand binding. Medicines targeting NHRs, utilized in clinical settings for conditions like inflammation and cancers, exploit their druggable nature. The endogenous degradation of NHRs via the ubiquitin-proteasome pathway remains unclear, driving our CRISPR-based screens to identify relevant ubiquitin ligases. Characterizing hits through biochemical and structural methods in our project opens a novel therapeutic avenue by targeting NHR degradation. NHR activity, tightly controlled by coregulators in a ligand-dependent manner, remains poorly understood, prompting our investigation into molecular details using advanced techniques. Our research combines biophysical, biochemical, and structural biology methods, including mass spectroscopy, mass photometry, next-gen sequencing, and cryo-EM, to illuminate the intricacies of NHR repression, activation, and their interaction with chromatin.