Endocrine Abstracts

Experimental results have shown that the presence of endocrine disrupting chemicals (EDCs) such as the diphenyl compound DDT and its analogue DDE, allosterically cause the release of the stably bound dihydrotestosterone (DHT) from the steroid binding site of the Androgen Receptor (AR) ligand binding domain. It was hypothesized that EDCs mediate this effect via binding to the Binding Function 3 (BF3) surface binding site. Mutations of three BF 3 amino acids (F673K, F673W, G724R, G724M, and L830D) showed that the ability of DDE to inhibit AR activity was reduced, suggesting that DDE binds to the BF 3 site and allosterically regulates AR activity. In this study, the Induced Fit Docking protocol of the Schrodinger software was used to dock DDE into the BF 3 site of the wild type AR ligand binding domain as well as the five mutant BF 3 sites. The docking poses generated for each receptor were clustered and representative structures were selected. The energy of interaction between DDE and the BF 3 site amino acids was evaluated for each of the selected docks of the wild type and mutant receptors. The relationship between the energies of interaction and the experimental results for DDE inhibition of the mutant AR activities is discussed. Additionally, stochastic dynamics were run on the wild type and mutant AR receptors using the Schrodinger software and the output was analyzed using the program Caver for the identification of potential exit channels for the bound steroid ligand. This analysis assesses the stability of the wild type and mutant AR receptors and indicates ways that the steroid may be able to unbind from the receptor in the presence of DDE in the BF3 site and how the mutations in the BF3 site affect that process.