Molecular analysis of androgen receptor mutants

Treatment-induced mutations in the ligand binding domain of the androgen receptor (AR) are known to change antagonists into agonists. Recently, the F877L mutation has been described to convert Enzalutamide (Enza) into an agonist. This mutation was seen to co-occur in the endogenous AR allele of the LNCaP cells, next to the T878A mutation. Here, we studied the effects of Enza on the F877L and T878A mutants, as well as the double mutant AR (F877L/T878A). Molecular modeling revealed favorable structural changes in the double mutant AR that lead to a decrease in steric clashes for Enza. Ligand binding assays confirmed that the F877L mutation leads to an increase in relative binding affinity for Enza, but only the combination with the T878A mutation resulted in a strong agonistic activity. This correlated with changes in co-regulator recruitment and chromatin interactions. Our data show that Enza is only a very weak partial agonist of the AR F877L, and a strong partial agonist of the double mutant AR.

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