Not to undermine the absolute horrible series of events occurring with the last post on here. We can all hope and pray. However I just found this and think it’s interesting especially the last sentence.
link to full article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571323/#idm139876385635328title
Structural basis of mutation-induced AR promiscuity
DHT-bound AR LBD T877A
The single point mutation T877A has been found in LNCaP cells and prostate cancer patients to confer abnormal binding characteristics to the AR. This mutation has been shown to cause a significant increase in the affinity of the AR for binding to estrogens and progesterone. In addition, this mutation also allows the AR to be activated by antiandrogens such as flutamide145,165. To understand the structural basis of this abnormal binding characteristic, Sack et al solved the crystal structure of the wild-type (WT) (PDB: 1I37) and T877A (PDB: 1I38) AR LBDs complexed with DHT67. A comparison of both structures revealed similar overall conformations. Interactions between DHT and both forms of the AR occur at almost identical points of contact, except at the mutated residue (Figure 7A). Interestingly, the introduction of the T877A mutation created additional space around the D-ring of DHT. This increase in volume allows bulkier ligands to enter the pocket, and this may induce AR promiscuity for other hormones and analogs, such as estrogens and progesterone. Conversely, the presence of T877 limits the pocket size and is thought to be important for ligand specificity. The concept that an increase in the LBP may increase ligand promiscuity was further supported by biochemical studies in which threonine was replaced by the larger amino acid aspartic acid, which prevented androgen binding, presumably by steric hindrance, making the mutant receptor unresponsive to androgen activation166.