Exploring the molecular basis of the Glucocorticoid Receptor-Cofactor interaction

ALVES, N. R. C.; PECCI, A.; ALVAREZ, L. D.

San Carlos de Bariloche

Simposio; Fourth South American Symposium in Signal Transduction and Molecular Medicine; 2018

Fourth South American Symposium in Signal Transduction and Molecular Medicine

Glucocorticoids (GCs) are a class of endogenous steroid hormones that influence the activity of virtually every mammalian cell, mainly by binding to the glucocorticoid receptor (GR). From a pharmacological perspective, synthetic GR agonists are among the most prescribed drugs worldwide. As the standard treatment for reducing inflammation and immune activation, they conform systemic therapies in nearly all medical specialties. Unfortunately, cumulative doses of GCs are linked to severe side effects. Conversely, antiglucocorticoids are often clinically used for excessive endogenous GCs production treatment, as occurring in GC induced hypertension or depression. GR is a modular protein organized into three major domains named N-terminal ligand-independent activation function-1 domain, central DNA-binding domain and C-terminal ligand-binding domain (LBD). The AF-2 domain is a hydrophobic cavity on the GR LBD surface where both coactivators and corepressors are specifically recruited through the recognition of LxxLL motifs (NR boxes). AF-2 domain shape is mainly determined by the H12 position, which in turn depends on the ligand structure. Thus, the relative affinities for different coregulators are intimately linked to the ligand. Here, in order to evaluate the ability of a set of well characterized GCs (full agonist,partial agonist and active and passive antagonists) to bind peptides containing diverse NR boxes, we used the Microarray Assay for Realtime Coregulator-Nuclear Receptor Interaction (MARCoNI). Then, aiming to stablish a correlation among peptide recruitment and ligand structure, we explored the molecular basis of GRLBD-cofactor interaction through a combination of computational modeling methods, taking as starting point the crystal structures of GR LBD in agonist and antagonist states. We believe that a better understanding of how ligands influence cofactors recruitment may improve the strategies for the rational design of new selective GCs drugs.