The AlphaFold predictive structure of the entire progesterone receptor with the region unique to isoform A highlighted in purple. Amino acids 1-164 are seen in grey as they are not included in isoform A. AlphaFold Identifier: AF-P060401-F
PR-A is 164 residues shorter than PR-B in humans[3] and anywhere from 128-165 residues shorter in other organisms.[4] Each isoform binds its natural ligand, progesterone, but also demonstrates the ability to bind a number of other agonists including norethindrone, a synthetic progestin.[5]
The crystallographic structure of the ligand-binding domain which is common to both isoforms A and B in its dimerized conformation (purple). Dimerization will only occur when a ligand is bound. The study which yielded this structure (Maduass et al. 2004) used agonists mometasone fuorate and norethindrone (grey) to induce dimerization. PBD Identifier: 1SQN
Expression and overexpression
PR-A and PR-B are generally expressed in equal ratios,[3] but PR-A is expressed in larger amounts in uterine stromal cells normally.[6] A spike in PR-A expression in the myometrium has been observed to initiate parturition in placental mammals.[7]
PR-A is the isoform most commonly observed to be overexpressed in human breast cancer. Currently PR is estimated by immunohistochemistry and earlier was quantified by standardized radio-ligand binding assays developed by New England Nuclear and Wittliff.[8] Patients with PR-A rich carcinomas, as opposed to patients with PR-B rich carcinomas, have faster recurrence rates.[9]
^Fisher, B., Redmond, C., Brown, A., Wickerham, D. L., Wolmark, N., Allegra, J. C., Escher, G., Lippman, M., Savlov, E., Wittliff, J. L. and Fisher, E. R. et al. Influence of Tumor Estrogen and Progesterone Receptor Levels on the Response to Tamoxifen and Chemotherapy in Primary Breast Cancer. J. Clin. Oncol., 1:227-241, 1983. https://pubmed.ncbi.nlm.nih.gov/6366135/
