Too many people to thank, but all this journey would not have been possible without the mentorship of Adali Pecci, Valeria Levi, the Gordon Hager lab, and crucial collaborations with the Estébanez-Perpiñá team, who joined us in this fight.
Special thanks to my PhD student, Agustina!

In summary
- GR is mostly dimeric upon ligand activation
- GR’s final conformation might be a tetramer
- GR-GR contacts depend on a complex, intertwined crosstalk within all structural domains: LBD, DBD, and likely the NTD
- Is transrepression necessary to explain GR action?

Finally, Eva and Pablo’s team were able to crystallize GR’s LBD in a tetrameric form, giving us a unique opportunity to probe and test different oligomerization surfaces on GR. They even managed to capture GR tetramers in vitro with a GR DBD-LBD fragment!

doi.org/10.1093/nar/...

By combing X-ray crystallography and live cell studies, Alba and Andrea were able to find new surfaces of GR-GR contacts, suggesting that several types of dimers can coexist in the cell

What was really missing, even though we already had live-cell experimental data, was the crystal structure of the tetramer. Here comes Eva and Pablo to the rescue!

The idea that GR is a tetramer was received with high skepticism, to put it mildly, even though we demonstrated increased transcriptional activity for a constitutive tetrameric mutant receptor (GRtetra),
www.genome.org/cgi/doi/10.1...

Back in 2016, we were able to quantify the oligomeric state of GR on a tandem array of DNA elements inside live cells, and we were shocked to find out that GR was actually a tetramer when bound to chromatin!
doi.org/10.1073/pnas...

Fast forward to 2021, we also found that a mostly monomeric GR mutant (GRmon) was unable to activate genes and bind to chromatin, suggesting that most of GR activity was done by GR dimers
dx.doi.org/10.1038/s414...

By 2014, we confirmed that the GRdim mutant, allegedly monomeric and thus the main evidential basis for the claim of monomeric GR action, was actually a dimer. Where are all the monomers?
doi.org/10.1371/jour...

In 2010, we applied the N&B assay to quantify, for the first time, the oligomeric state of GR in live cells. Surprisingly, we find that the population of GR is mostly dimeric in the nucleus. Where are all the monomers?
doi.org/10.1371/jour...

This paper marks the culmination of a 15-year (and 7 papers) journey to challenge #Glucocorticoid-Receptor(GR) dogma. The classic paradigm of GR action states that monomeric GR and dimeric GR regulate a different set of genes

Gracias Pablo!