THE MOLECULAR-BASIS OF RU486 RESISTANCE IN THE TAMMAR WALLABY, MACROPUS-EUGENII

RU486 acts as a potent anti-progestin in humans but does not antagonis e progesterone action in the chicken or hamster reflecting a substitut ion in the ligand binding domain (LED) of cysteine for glycine in both the chicken and the hamster progesterone receptor (PR), at the positi on corresponding to codon 722 of the human PR. The tammar wallaby, Mac ropus eugenii, is also resistant to the effects of RU486. Cloning of a partial cDNA of the PR in the tammar wallaby reveals a glycine to ala nine substitution (gly 722 in the human PR), as well as a glutamine to histidine substitution two amino acids upstream of this alanine resid ue. Both the glycine and glutamine residues are substituted in all thr ee resistant species. These substitutions are also found in the minera locorticoid receptor, which also does not bind RU486, and suggest an i mportant role for these residues in the formation of the 11-beta pocke t of the receptor, which accommodates the bulky side-chains of 11-beta substituted steroids.