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PDBsum entry 2q7j

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protein ligands Protein-protein interface(s) links
Hormone PDB id
2q7j
Jmol
Contents
Protein chains
247 a.a. *
13 a.a. *
Ligands
SO4
TES
GOL
Waters ×158
* Residue conservation analysis
PDB id:
2q7j
Name: Hormone
Title: The wild type androgen receptor ligand binding domain bound testosterone and a tif2 box 3 coactivator peptide 740-753
Structure: Androgen receptor. Chain: a. Synonym: dihydrotestosterone receptor. Engineered: yes. Nuclear receptor coactivator 2. Chain: b. Synonym: ncoa-2, transcriptional intermediary factor 2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ar, dhtr, nr3c4. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: ncoa2, tif2. Expression_system_taxid: 562
Resolution:
1.90Å     R-factor:   0.182     R-free:   0.220
Authors: R.T.Gampe
Key ref:
E.B.Askew et al. (2007). Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone. J Biol Chem, 282, 25801-25816. PubMed id: 17591767 DOI: 10.1074/jbc.M703268200
Date:
07-Jun-07     Release date:   24-Jul-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P10275  (ANDR_HUMAN) -  Androgen receptor
Seq:
Struc:
 
Seq:
Struc:
919 a.a.
247 a.a.
Protein chain
Pfam   ArchSchema ?
Q15596  (NCOA2_HUMAN) -  Nuclear receptor coactivator 2
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1464 a.a.
13 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: 10.1074/jbc.M703268200 J Biol Chem 282:25801-25816 (2007)
PubMed id: 17591767  
 
 
Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone.
E.B.Askew, R.T.Gampe, T.B.Stanley, J.L.Faggart, E.M.Wilson.
 
  ABSTRACT  
 
The androgen receptor (AR) is transcriptionally activated by high affinity binding of testosterone (T) or its 5alpha-reduced metabolite, dihydrotestosterone (DHT), a more potent androgen required for male reproductive tract development. The molecular basis for the weaker activity of T was investigated by determining T-bound ligand binding domain crystal structures of wild-type AR and a prostate cancer somatic mutant complexed with the AR FXXLF or coactivator LXXLL peptide. Nearly identical interactions of T and DHT in the AR ligand binding pocket correlate with similar rates of dissociation from an AR fragment containing the ligand binding domain. However, T induces weaker AR FXXLF and coactivator LXXLL motif interactions at activation function 2 (AF2). Less effective FXXLF motif binding to AF2 accounts for faster T dissociation from full-length AR. T can nevertheless acquire DHT-like activity through an AR helix-10 H874Y prostate cancer mutation. The Tyr-874 mutant side chain mediates a new hydrogen bonding scheme from exterior helix-10 to backbone protein core helix-4 residue Tyr-739 to rescue T-induced AR activity by improving AF2 binding of FXXLF and LXXLL motifs. Greater AR AF2 activity by improved core helix interactions is supported by the effects of melanoma antigen gene protein-11, an AR coregulator that binds the AR FXXLF motif and targets AF2 for activation. We conclude that T is a weaker androgen than DHT because of less favorable T-dependent AR FXXLF and coactivator LXXLL motif interactions at AF2.
 
  Selected figure(s)  
 
Figure 8.
FIGURE 8. Potential A-ring and water mediated H-bonding schemes for T and DHT. Predicted A-ring H-bond distances and angles are shown based on the tetrahedral geometry of conserved structural water HOH1 (see Footnote 3 and see Table 4). Arrowhead with black dashed lines indicate the direction of donated H-bonds and orange dashed lines designate potential interactions with neighboring polar atoms of WT AR LBD bound to T and AR-(20-30) FXXLF peptide (tan) (A); WT AR LBD bound to DHT and GRIP-1-(740-752) LXXLL peptide (green) (42) (B); and the superimposition of A and B (C). Superior hydrophilic properties and a shorter distance are thought to enhance the HOH1 to T 3-keto O H-bond over that in DHT.
Figure 11.
FIGURE 11. Structural differences between the steroid and nonsteroidal ligand binding pockets. Superimposition of WT AR LBD crystal structures bound with an FXXLF peptide and T (brown), DHT (green) (18), R1881 (magenta) (4), and S-1 bicalutamide agonist analog (cyan) (43) and AR-H874Y LBD bound to the AR FXXLF peptide and T (yellow). The C-19 bridgehead methyl group on T and DHT forces the Met-745 and Trp-741 side chains away from the steroid A-ring. For R1881 and S-1, the absence of an equivalent methyl group allows these side chains to adopt different rotamers that fill the vacated space above ring A^4. The para-fluoro phenyl group on S1 extends into the space between helix-12 Met-895 and helix-5 Met-742 and directs Trp-741 to a third unique conformation. Appropriate para-phenyl substituents are thought to stabilize the AR LBD core by interacting with HOH3 (43).
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 25801-25816) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21228820 C.K.Ho, and F.K.Habib (2011).
Estrogen and androgen signaling in the pathogenesis of BPH.
  Nat Rev Urol, 8, 29-41.  
21280043 D.A.Simmons, and P.Yahr (2011).
Nitric oxidergic cells related to ejaculation in gerbil forebrain contain androgen receptor and respond to testosterone.
  J Comp Neurol, 519, 900-915.  
20690138 D.J.van de Wijngaart, H.J.Dubbink, M.Molier, C.de Vos, G.Jenster, and J.Trapman (2011).
Inhibition of androgen receptor functions by gelsolin FxxFF peptide delivered by transfection, cell-penetrating peptides, and lentiviral infection.
  Prostate, 71, 241-253.  
21070525 M.T.Rosenberg, M.Froehner, D.Albala, and M.M.Miner (2010).
Biology and natural history of prostate cancer and the role of chemoprevention.
  Int J Clin Pract, 64, 1746-1753.  
19372581 A.R.Karpf, S.Bai, S.R.James, J.L.Mohler, and E.M.Wilson (2009).
Increased expression of androgen receptor coregulator MAGE-11 in prostate cancer by DNA hypomethylation and cyclic AMP.
  Mol Cancer Res, 7, 523-535.  
19828458 E.B.Askew, S.Bai, A.T.Hnat, J.T.Minges, and E.M.Wilson (2009).
Melanoma antigen gene protein-A11 (MAGE-11) F-box links the androgen receptor NH2-terminal transactivation domain to p160 coactivators.
  J Biol Chem, 284, 34793-34808.  
19721807 G.N.Brooke, and C.L.Bevan (2009).
The role of androgen receptor mutations in prostate cancer progression.
  Curr Genomics, 10, 18-25.  
19676093 J.P.Sedelaar, and J.T.Isaacs (2009).
Tissue culture media supplemented with 10% fetal calf serum contains a castrate level of testosterone.
  Prostate, 69, 1724-1729.  
19198621 W.P.Harris, E.A.Mostaghel, P.S.Nelson, and B.Montgomery (2009).
Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion.
  Nat Clin Pract Urol, 6, 76-85.  
18337247 C.Mao, N.M.Patterson, M.T.Cherian, I.O.Aninye, C.Zhang, J.B.Montoya, J.Cheng, K.S.Putt, P.J.Hergenrother, E.M.Wilson, A.M.Nardulli, S.K.Nordeen, and D.J.Shapiro (2008).
A new small molecule inhibitor of estrogen receptor alpha binding to estrogen response elements blocks estrogen-dependent growth of cancer cells.
  J Biol Chem, 283, 12819-12830.  
  18612376 F.Claessens, S.Denayer, N.Van Tilborgh, S.Kerkhofs, C.Helsen, and A.Haelens (2008).
Diverse roles of androgen receptor (AR) domains in AR-mediated signaling.
  Nucl Recept Signal, 6, e008.  
18037956 G.N.Brooke, M.G.Parker, and C.L.Bevan (2008).
Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression.
  Oncogene, 27, 2941-2950.  
18438176 J.A.Sarvis, and I.M.Thompson (2008).
Androgens and prevention of prostate cancer.
  Curr Opin Endocrinol Diabetes Obes, 15, 271-277.  
18780294 J.K.Scariano, E.Treat, F.Alba, H.Nelson, S.A.Ness, and A.Y.Smith (2008).
The SRD5A2 V89L polymorphism is associated with severity of disease in men with early onset prostate cancer.
  Prostate, 68, 1798-1805.  
18511414 L.A.Ponguta, C.W.Gregory, F.S.French, and E.M.Wilson (2008).
Site-specific androgen receptor serine phosphorylation linked to epidermal growth factor-dependent growth of castration-recurrent prostate cancer.
  J Biol Chem, 283, 20989-21001.  
18212060 S.Bai, and E.M.Wilson (2008).
Epidermal-growth-factor-dependent phosphorylation and ubiquitinylation of MAGE-11 regulates its interaction with the androgen receptor.
  Mol Cell Biol, 28, 1947-1963.  
18048459 S.Bai, G.Grossman, L.Yuan, B.A.Lessey, F.S.French, S.L.Young, and E.M.Wilson (2008).
Hormone control and expression of androgen receptor coregulator MAGE-11 in human endometrium during the window of receptivity to embryo implantation.
  Mol Hum Reprod, 14, 107-116.  
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.