Postdoc position in Receptores de andrógenos y de glucocorticoides (POST16322122023): actividades cruzadas y oligomerizacion

We have gathered solid preliminary evidence in support of an Androgen receptor-Glucocorticoid receptor AR·GR heterodimer, results that are the initial cornerstone of this project. The overall functions of the candidate chosen will be aimed at determining the atomic and molecular determinants underlying formation of an AR·GR heterodimer and explore its functional impact as a mechanism driving resistance to current antiandrogens and GCs. Each Aim encloses both structural and functional sub-objectives. Complementary techniques will be used in an orthogonal manner throughout. The concrete tasks are:

• To determine binding and kinetic constants of peptides derived from both the AR-LBD and GR-LBD for the immobilized domains, as well as for ‘core’ AR and GR (i.e., multidomain forms comprising DBD, hinge and LBD moieties) in solution. Peptide binders will be identified and used in the X-ray objective.
• To determine binding and kinetic constants of the GR-LBD·AR-LBD heterodimer as well as of the AR·GR cores. (How do these constants compare with those of the respective homodimers (LBDs and multi-domain proteins)? Compare affinities with those of GR·PR, GR·ER and AR·ER LBD atypical heterodimers, and data in our recent papers of GR-MR interactions
• To determine the binding and kinetic constants of the GR-LBD·AR-LBD heterodimer as well as of the AR·GR cores in the presence of small-molecule drugs (e.g., enzalutamide, abiraterone and GCs (Dex)).
• To characterize AR·GR physical interactions in living cells.
• To determine the binding and kinetic constants of the GR-LBD·AR-LBD heterodimer and of AR·GR cores that feature mutations identified in PCa, AIS or Chrousos syndrome patients.
• To analyze how AR and GR LBDs communicate with each other using a battery of crosslinkers. Assess the possible impact of disease-linked mutations and of pharmaceutical drugs on these cross-talks.
• To analyze how DBD, hinge and LBD moieties of AR and GR communicate with each other and with cognate DNA using a battery of crosslinkers. Assess the possible impact of disease-linked mutations and of pharmaceutical drugs on crosstalks.
• To solve the crystal structures of AR-LBD complexed to GR-derived peptides and of GR-LBD in complex with AR peptides.
• To solve the crystal structures of the AR-LBD·GR-LBD heterodimer.
• To identify hotspots and energetic parameters for AR·GR heterodimerization (in ollaboration).
• To study the impact of disease-linked mutations on AR and GR oligomerization (in collaboration).
• To determine the 3D structure of the AR·GR heterodimer and to compare it to those recently published of GR and AR homodimers.