Characterization of TSG101 Induced Allostery within Glucocorticoid Receptor and Computational Drug-Lead Targeting of the Glucocorticoid Receptor DNA-Binding Domain

[摘要] Glucocorticoid Receptor (GR) is a typical steroid hormone receptor. GR has a disordered N-terminal domain that binds transcriptional cofactors, a DNA-binding domain, and a steroid binding domain. Most work for the past forty years has been focused on the latter two domains that are structured and amenable to characterization. Yet, the disordered N-terminus makes up more than half of the protein and is absolutely required for transcriptional activation (repression can occur regardless). There are also translational isoforms with truncated N-termini that alter the resulting activity of GR. How the disordered isoforms of the N-terminus couple to cofactors and transcriptional activity is currently unclear. In this thesis, I sought organizing principles to explain the varying activities of GR translational isoforms. I found that a transcriptional cofactor, tumor susceptibility gene 101 (TSG101), can bind and fold the disordered N-terminus of GR. TSG101;;s binding is allosterically coupled to binding of DNA, but the exact mechanism differs between different isoforms of GR. In this thesis I also characterized the thermodynamic stability of the TSG101 coiled-coil, which binds GR, and I used computational docking to develop novel drug-leads targeted against the GR DNA-binding domain.

[发布机构] Johns Hopkins University

[效力级别] tumor susceptibility gene-101

[关键词] glucocorticoid receptor;tumor susceptibility gene-101;transcription;binding;allostery;Biology