We investigated progestin and corticosteroid activation of the progesterone receptor (PR) from elephant shark (Callorhinchus milii), a cartilaginous fish belonging to the oldest group of jawed vertebrates. Comparison with human PR experiments provides insights into the evolution of steroid activation of human PR. At 1 nM steroid, elephant shark PR is activated by progesterone, 17-hydroxy-progesterone, 20beta-hydroxy-progesterone, 11-deoxycorticosterone (21-hydroxyprogesterone) and 11-deoxycortisol. At 1 nM steroid, human PR is activated only by progesterone and11-deoxycorticosterone indicating increased specificity for progestins and corticosteroids during the evolution of human PR. RU486, an important clinical antagonist of human PR, did not inhibit progesterone activation of elephant shark PR. Cys-528 in elephant shark PR corresponds to Gly-722 in human PR, which is essential for RU486 inhibition of human PR. Confirming the importance of this site on elephant shark PR, RU486 inhibited progesterone activation of the Cys528Gly mutant PR. There also was a decline in activation of elephant shark Cys528Gly PR by 11-deoxycortisol, 17-hydroxy-progesterone and 20beta-hydroxy-progesterone and an increase in activation of human Gly722Cys PR by 11-deoxycortisol and decreased activation by corticosterone. One or more of these changes may have selected for the mutation corresponding to human glycine-722 PR that first evolved in platypus PR, a basal mammal.
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