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PDBsum entry 2pnu

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Hormone/gene regulation PDB id
2pnu
Jmol
Contents
Protein chain
245 a.a. *
Ligands
SO4
ENM
DTT
MES
Waters ×201
* Residue conservation analysis
PDB id:
2pnu
Name: Hormone/gene regulation
Title: Crystal structure of human androgen receptor ligand-binding domain in complex with em-5744
Structure: Androgen receptor. Chain: a. Fragment: ligand binding domain. Synonym: dihydrotestosterone receptor. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ar, dhtr, nr3c4. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
1.65Å     R-factor:   0.183     R-free:   0.205
Authors: L.Cantin,F.Faucher,J.F.Couture,K.Pereira De Jesus-Tran, P.Legrand,C.L.Ciobanu,S.M.Singh,F.Labrie,R.Breton
Key ref:
L.Cantin et al. (2007). Structural characterization of the human androgen receptor ligand-binding domain complexed with EM5744, a rationally designed steroidal ligand bearing a bulky chain directed toward helix 12. J Biol Chem, 282, 30910-30919. PubMed id: 17711855 DOI: 10.1074/jbc.M705524200
Date:
25-Apr-07     Release date:   11-Sep-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P10275  (ANDR_HUMAN) -  Androgen receptor
Seq:
Struc:
 
Seq:
Struc:
919 a.a.
245 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.M705524200 J Biol Chem 282:30910-30919 (2007)
PubMed id: 17711855  
 
 
Structural characterization of the human androgen receptor ligand-binding domain complexed with EM5744, a rationally designed steroidal ligand bearing a bulky chain directed toward helix 12.
L.Cantin, F.Faucher, J.F.Couture, K.P.de Jésus-Tran, P.Legrand, L.C.Ciobanu, Y.Fréchette, R.Labrecque, S.M.Singh, F.Labrie, R.Breton.
 
  ABSTRACT  
 
Antiandrogens are commonly used to treat androgen-dependent disorders. The currently used drugs unfortunately possess very weak affinity for the human AR (hAR), thus indicating the need to develop new high-affinity steroidal antiandrogens. Our compounds are specially designed to impede repositioning of the mobile carboxyl-terminal helix 12, which blocks the ligand-dependent transactivation function (AF-2) located in the AR ligand-binding domain (ARLBD). Using crystal structures of the hARLBD, we first found that H12 could be directly reached from the ligand-binding pocket (LBP) by a chain positioned on the C18 atom of an androgen steroid nucleus. A set of 5alpha-dihydrotestosterone-derived molecules bearing various C18 chains were thus synthesized and tested for their capacity to bind hAR and act as antagonists. Although most of those having very high affinity for hAR were agonists, several very potent antagonists were obtained, confirming the structural importance of the C18 chain. To understand the role of the C18 chain in their agonistic/antagonistic properties, the structure of the hARLBD complexed with one of these agonists, EM5744, was determined at a 1.65-A resolution. We have identified new interactions involving Gln(738), Met(742), and His(874) that explain both the high affinity of this compound and the inability of its bulky chain to prevent the repositioning of H12. This structural information will be helpful to refine the structure of the chains placed on the C18 atom to obtain efficient H12-directed steroidal antiandrogens.
 
  Selected figure(s)  
 
Figure 1.
FIGURE 1. Molecular structures of the hAR ligands used in this study. DHT, THG, and EM5744 are colored using the standard CPK color set (carbon atoms are depicted in light gray, oxygen atoms in red, and fluorine atoms in light green). For DHT, carbon and oxygen atoms are numbered according to the standard steroid nomenclature, the rings designated by letters and the faces of the steroid labeled and . For THG, the extra C17 -ethyl and C18-methyl groups are identified. For EM5744, the model shows the C18-[2-(3,5-difluoro-benzyloxy)-methyl] side chain.
Figure 6.
FIGURE 6. Expansion of the LBP of the hAR in the presence of EM5744. Close-up view of a superposition of the hAR structures in complex with EM5744 (light gray), DHT (red, PDB entry 2AMA (23)), and THG (green, PDB entry 2AMB (23)) showing how the hAR expands its binding cavity to accommodate ligands with much larger sizes. This mainly occurs via a re-orientation of the side chain of only 2 residues, namely those of Trp^741 (H3) and Met^895 (H12). The surface of the EM5744 binding pocket (in light blue) was calculated with the Swiss-Pdb Viewer program (45) and the figure rendered with Pov-Ray (47). The bound EM5744 is depicted in space-filling form and in standard CPK colors.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 30910-30919) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19796750 Y.Chen, N.J.Clegg, and H.I.Scher (2009).
Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target.
  Lancet Oncol, 10, 981-991.  
18273598 L.Rinnab, A.Hessenauer, S.V.Schütz, E.Schmid, R.Küfer, F.Finter, R.E.Hautmann, K.D.Spindler, and M.V.Cronauer (2008).
[Role of androgen receptors in hormone-refractory prostate cancer: molecular basics and experimental therapy approaches]
  Urologe A, 47, 314-325.  
18391212 S.M.Soisson, G.Parthasarathy, A.D.Adams, S.Sahoo, A.Sitlani, C.Sparrow, J.Cui, and J.W.Becker (2008).
Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation.
  Proc Natl Acad Sci U S A, 105, 5337-5342.
PDB code: 3bej
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