Isoform of the progesterone receptor
Theprogesterone receptor A (PR-A ) is one of three knownisoforms of theprogesterone receptor (PR), the mainbiological target of theendogenous progestogen sex hormone progesterone .[ 1] [ 2] PR-B andPR-C .[ 1] [ 2]
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] [ 4] [ 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 [ edit ] PR-A and PR-B are generally expressed in equal ratios,[ 3] [ 6] [ 7]
PR-A is the isoform most commonly observed to be overexpressed in human breast cancer and patients with PR-A rich carcinomas, as opposed to patients with PR-B rich carcinomas, have faster recurrence rates.[ 8]
^a b Jacobsen BM, Horwitz KB (2012)."Progesterone receptors, their isoforms and progesterone regulated transcription" .Mol. Cell. Endocrinol .357 (1– 2):18– 29.doi :10.1016/j.mce.2011.09.016 .PMC 3272316 PMID 21952082 . ^a b Scarpin KM, Graham JD, Mote PA, Clarke CL (2009)."Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression" .Nucl Recept Signal .7 : e009.doi :10.1621/nrs.07009 .PMC 2807635 PMID 20087430 . ^a b Graham, J Dinny; Clarke, Christine L (October 2002)."Progesterone receptors - animal models and cell signaling in breast cancer: Expression and transcriptional activity of progesterone receptor A and progesterone receptor B in mammalian cells" .Breast Cancer Research .4 (5):187– 190.doi :10.1186/bcr450 ISSN 1465-542X .PMC 138742 PMID 12223122 . ^ Conneely, O (November 2000)."Progesterone receptors in reproduction: functional impact of the A and B isoforms" .Steroids .65 (10– 11):571– 577.doi :10.1016/S0039-128X(00)00115-X .PMID 11108861 . ^ Madauss, Kevin P.; Deng, Su-Jun; Austin, Robert J. H.; Lambert, Millard H.; McLay, Iain; Pritchard, John; Short, Steven A.; Stewart, Eugene L.; Uings, Ian J.; Williams, Shawn P. (2004-06-01)."Progesterone Receptor Ligand Binding Pocket Flexibility: Crystal Structures of the Norethindrone and Mometasone Furoate Complexes" .Journal of Medicinal Chemistry .47 (13):3381– 3387.doi :10.1021/jm030640n .ISSN 0022-2623 .PMID 15189034 . ^ Bulun, Serdar E.; Cheng, You-Hong; Yin, Ping; Imir, Gonca; Utsunomiya, Hiroki; Attar, Erkut; Innes, Joy; Julie Kim, J. (March 2006)."Progesterone resistance in endometriosis: Link to failure to metabolize estradiol" .Molecular and Cellular Endocrinology .248 (1– 2):94– 103.doi :10.1016/j.mce.2005.11.041 .PMID 16406281 . ^ Cope, Dominique; Monsivais, Diana (2022-04-27)."Progesterone Receptor Signaling in the Uterus Is Essential for Pregnancy Success" .Cells .11 (9): 1474.doi :10.3390/cells11091474 ISSN 2073-4409 .PMC 9104461 PMID 35563781 . ^ Timmermans-Sprang, Elpetra P. M.; Gracanin, Ana; Mol, Jan A. (2017-04-13)."Molecular Signaling of Progesterone, Growth Hormone, Wnt, and HER in Mammary Glands of Dogs, Rodents, and Humans: New Treatment Target Identification" .Frontiers in Veterinary Science .4 : 53.doi :10.3389/fvets.2017.00053 ISSN 2297-1769 .PMC 5389977 PMID 28451590 .
(1) Basic domains
(1.1) Basic leucine zipper (bZIP )(1.2) Basic helix-loop-helix (bHLH )
Group A Group B Group CPAS Group D Group E Group F
(1.3) bHLH-ZIP (1.4) NF-1 (1.5) RF-X (1.6) Basic helix-span-helix (bHSH)
(2.1) Nuclear receptor (Cys4 )
subfamily 1 subfamily 2 subfamily 3 subfamily 4 subfamily 5 subfamily 6 subfamily 0
(2.2) Other Cys4 (2.3) Cys2 His2 (2.4) Cys6 (2.5) Alternating composition (2.6) WRKY
(4)β-Scaffold factors with minor groove contacts
(0) Other transcription factors
PR Tooltip Progesterone receptor
Agonists Testosterone derivatives: Progestins:6,6-Difluoronorethisterone 6,6-Difluoronorethisterone acetate 17α-Allyl-19-nortestosterone Allylestrenol Altrenogest Chloroethynylnorgestrel Cingestol Danazol Desogestrel Dienogest Ethinylandrostenediol Ethisterone Ethynerone Etonogestrel Etynodiol Etynodiol diacetate Gestodene Gestrinone Levonorgestrel Levonorgestrel esters (e.g.,levonorgestrel butanoate )Lynestrenol Lynestrenol phenylpropionate Metynodiol Metynodiol diacetate Norelgestromin Norethisterone (norethindrone) Norethisterone esters (e.g.,norethisterone acetate ,norethisterone enanthate )Noretynodrel Norgesterone Norgestimate Norgestrel Norgestrienone Norvinisterone Oxendolone Quingestanol Quingestanol acetate Tibolone Tigestol Tosagestin ; Anabolic–androgenic steroids:11β-Methyl-19-nortestosterone 11β-Methyl-19-nortestosterone dodecylcarbonate 19-Nor-5-androstenediol 19-Nor-5-androstenedione 19-Nordehydroepiandrosterone Bolandiol Bolandiol dipropionate Bolandione Dimethisterone Dienedione Dienolone Dimethandrolone Dimethandrolone buciclate Dimethandrolone dodecylcarbonate Dimethandrolone undecanoate Dimethyldienolone Dimethyltrienolone Ethyldienolone Ethylestrenol (ethylnandrol) Methyldienolone Metribolone (R-1881) Methoxydienone (methoxygonadiene) Mibolerone Nandrolone Nandrolone esters (e.g.,nandrolone decanoate ,nandrolone phenylpropionate )Norethandrolone Normethandrone (methylestrenolone, normethandrolone, normethisterone) RU-2309 Tetrahydrogestrinone Trenbolone (trienolone) Trenbolone esters (e.g.,trenbolone acetate ,trenbolone enanthate )Trendione Trestolone Trestolone acetate MixedSPRMs Tooltip Selective progesterone receptor modulators ) Antagonists
mPR Tooltip Membrane progesterone receptor PAQR Tooltip Progestin and adipoQ receptor )
