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PDBsum entry 2ovm

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protein ligands Protein-protein interface(s) links
Transcription PDB id
2ovm
Jmol
Contents
Protein chains
243 a.a. *
11 a.a. *
Ligands
AS0
Waters ×59
* Residue conservation analysis
PDB id:
2ovm
Name: Transcription
Title: Progesterone receptor with bound asoprisnil and a peptide from the co-repressor ncor
Structure: Progesterone receptor. Chain: a. Fragment: ligand binding domain (residues 678-933). Synonym: pr. Engineered: yes. Ncor. Chain: b. Fragment: residues 2251-2275. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pgr, nr3c3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: synthesized peptide
Resolution:
2.60Å     R-factor:   0.219     R-free:   0.244
Authors: K.P.Madauss,S.-J.Deng,S.A.Short,E.L.Stewart,S.P.Williams
Key ref: K.P.Madauss et al. (2007). A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator. Mol Endocrinol, 21, 1066-1081. PubMed id: 17356170 DOI: 10.1210/me.2006-0524
Date:
14-Feb-07     Release date:   20-Mar-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P06401  (PRGR_HUMAN) -  Progesterone receptor
Seq:
Struc:
 
Seq:
Struc:
933 a.a.
243 a.a.
Protein chain
No UniProt id for this chain
Struc: 11 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     steroid hormone mediated signaling pathway   2 terms 
  Biochemical function     DNA binding     3 terms  

 

 
DOI no: 10.1210/me.2006-0524 Mol Endocrinol 21:1066-1081 (2007)
PubMed id: 17356170  
 
 
A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator.
K.P.Madauss, E.T.Grygielko, S.J.Deng, A.C.Sulpizio, T.B.Stanley, C.Wu, S.A.Short, S.K.Thompson, E.L.Stewart, N.J.Laping, S.P.Williams, J.D.Bray.
 
  ABSTRACT  
 
Selective progesterone receptor modulators (SPRMs) have been suggested as therapeutic agents for treatment of gynecological disorders. One such SPRM, asoprisnil, was recently in clinical trials for treatment of uterine fibroids and endometriosis. We present the crystal structures of progesterone receptor (PR) ligand binding domain complexed with asoprisnil and the corepressors nuclear receptor corepressor (NCoR) and SMRT. This is the first report of steroid nuclear receptor crystal structures with ligand and corepressors. These structures show PR in a different conformation than PR complexed with progesterone (P4). We profiled asoprisnil in PR-dependent assays to understand further the PR-mediated mechanism of action. We confirmed previous findings that asoprisnil demonstrated antagonism, but not agonism, in a PR-B transfection assay and the T47D breast cancer cell alkaline phosphatase activity assay. Asoprisnil, but not RU486, weakly recruited the coactivators SRC-1 and AIB1. However, asoprisnil strongly recruited the corepressor NCoR in a manner similar to RU486. Unlike RU486, NCoR binding to asoprisnil-bound PR could be displaced with equal affinity by NCoR or TIF2 peptides. We further showed that it weakly activated T47D cell gene expression of Sgk-1 and PPL and antagonized P4-induced expression of both genes. In rat leiomyoma ELT3 cells, asoprisnil demonstrated partial P4-like inhibition of cyclooxygenase (COX) enzymatic activity and COX-2 gene expression. In the rat uterotrophic assay, asoprisnil demonstrated no P4-like ability to oppose estrogen. Our data suggest that asoprisnil differentially recruits coactivators and corepressors compared to RU486 or P4, and this specific cofactor interaction profile is apparently insufficient to oppose estrogenic activity in rat uterus.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20333619 A.S.Veleiro, L.D.Alvarez, S.L.Eduardo, and G.Burton (2010).
Structure of the glucocorticoid receptor, a flexible protein that can adapt to different ligands.
  ChemMedChem, 5, 649-659.  
20543827 A.le Maire, C.Teyssier, C.Erb, M.Grimaldi, S.Alvarez, A.R.de Lera, P.Balaguer, H.Gronemeyer, C.A.Royer, P.Germain, and W.Bourguet (2010).
A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor.
  Nat Struct Mol Biol, 17, 801-807.
PDB codes: 3kmr 3kmz
20581824 C.A.Phelan, R.T.Gampe, M.H.Lambert, D.J.Parks, V.Montana, J.Bynum, T.M.Broderick, X.Hu, S.P.Williams, R.T.Nolte, and M.A.Lazar (2010).
Structure of Rev-erbalpha bound to N-CoR reveals a unique mechanism of nuclear receptor-co-repressor interaction.
  Nat Struct Mol Biol, 17, 808-814.
PDB code: 3n00
  20414842 N.Chegini (2010).
Proinflammatory and profibrotic mediators: principal effectors of leiomyoma development as a fibrotic disorder.
  Semin Reprod Med, 28, 180-203.  
19211567 H.Abdel-Hafiz, M.L.Dudevoir, and K.B.Horwitz (2009).
Mechanisms underlying the control of progesterone receptor transcriptional activity by SUMOylation.
  J Biol Chem, 284, 9099-9108.  
19372222 H.C.Raaijmakers, J.E.Versteegh, and J.C.Uitdehaag (2009).
The X-ray structure of RU486 bound to the progesterone receptor in a destabilized agonistic conformation.
  J Biol Chem, 284, 19572-19579.
PDB code: 2w8y
19333551 S.Ellmann, H.Sticht, F.Thiel, M.W.Beckmann, R.Strick, and P.L.Strissel (2009).
Estrogen and progesterone receptors: from molecular structures to clinical targets.
  Cell Mol Life Sci, 66, 2405-2426.  
19651637 S.W.Guo (2009).
Epigenetics of endometriosis.
  Mol Hum Reprod, 15, 587-607.  
18281245 A.Morikawa, N.Ohara, Q.Xu, K.Nakabayashi, D.A.DeManno, K.Chwalisz, S.Yoshida, and T.Maruo (2008).
Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer.
  Hum Reprod, 23, 944-951.  
18363513 C.Möller, J.Hoffmann, T.A.Kirkland, and W.Schwede (2008).
Investigational developments for the treatment of progesterone-dependent diseases.
  Expert Opin Investig Drugs, 17, 469-479.  
19000019 K.Levitsky, P.Szymanski, F.Jin, J.A.Meurer-Ogden, and R.N.Harkins (2008).
Development and Validation of an Improved Inducer-Regulator Protein Complex in the pBRES-Regulated Expression System.
  Hum Gene Ther, 19, 1273-1282.  
18852122 M.C.Hodgson, H.C.Shen, A.N.Hollenberg, and S.P.Balk (2008).
Structural basis for nuclear receptor corepressor recruitment by antagonist-liganded androgen receptor.
  Mol Cancer Ther, 7, 3187-3194.  
19072476 S.Ouzounian, P.Bouchard, and N.Chabbert-Buffet (2008).
Effects of antiprogestins on the uterus.
  Womens Health (Lond Engl), 4, 269-280.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.