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PDBsum entry 2ama

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protein ligands links
Hormone/growth factor receptor PDB id
2ama
Jmol PyMol
Contents
Protein chain
243 a.a. *
Ligands
SO4
DHT
Waters ×95
* Residue conservation analysis
PDB id:
2ama
Name: Hormone/growth factor receptor
Title: Crystal structure of human androgen receptor ligand binding domain in complex with dihydrotestosterone
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. Expression_system_taxid: 562.
Resolution:
1.90Å     R-factor:   0.214     R-free:   0.241
Authors: K.Pereira De Jesus-Tran,P.-L.Cote,L.Cantin,J.Blanchet, F.Labrie,R.Breton
Key ref:
K.Pereira de Jésus-Tran et al. (2006). Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity. Protein Sci, 15, 987-999. PubMed id: 16641486 DOI: 10.1110/ps.051905906
Date:
09-Aug-05     Release date:   16-May-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P10275  (ANDR_HUMAN) -  Androgen receptor
Seq:
Struc:
 
Seq:
Struc:
919 a.a.
243 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     2 terms  

 

 
DOI no: 10.1110/ps.051905906 Protein Sci 15:987-999 (2006)
PubMed id: 16641486  
 
 
Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity.
K.Pereira de Jésus-Tran, P.L.Côté, L.Cantin, J.Blanchet, F.Labrie, R.Breton.
 
  ABSTRACT  
 
Androgens exert their effects by binding to the highly specific androgen receptor (AR). In addition to natural potent androgens, AR binds a variety of synthetic agonist or antagonist molecules with different affinities. To identify molecular determinants responsible for this selectivity, we have determined the crystal structure of the human androgen receptor ligand-binding domain (hARLBD) in complex with two natural androgens, testosterone (Testo) and dihydrotestosterone (DHT), and with an androgenic steroid used in sport doping, tetrahydrogestrinone (THG), at 1.64, 1.90, and 1.75 A resolution, respectively. Comparison of these structures first highlights the flexibility of several residues buried in the ligand-binding pocket that can accommodate a variety of ligand structures. As expected, the ligand structure itself (dimension, presence, and position of unsaturated bonds that influence the geometry of the steroidal nucleus or the electronic properties of the neighboring atoms, etc.) determines the number of interactions it can make with the hARLBD. Indeed, THG--which possesses the highest affinity--establishes more van der Waals contacts with the receptor than the other steroids, whereas the geometry of the atoms forming electrostatic interactions at both extremities of the steroid nucleus seems mainly responsible for the higher affinity measured experimentally for DHT over Testo. Moreover, estimation of the ligand-receptor interaction energy through modeling confirms that even minor modifications in ligand structure have a great impact on the strength of these interactions. Our crystallographic data combined with those obtained by modeling will be helpful in the design of novel molecules with stronger affinity for the AR.
 
  Selected figure(s)  
 
Figure 1.
Molecular structures of the ligands used. DHT, dihydrotestosterone; Testo, testosterone; THG, tetrahydrogestrinone; R1881, methyltrienolone. Carbon and oxygen atoms of the steroids are numbered according to the standard steroid nomenclature and the cycles designated by letters. For THG, extra carbon atoms are numbered 20 and 21 for the 17[alpha]-ethyl group and 22 for the C18-methyl group.
Figure 5.
Double or unique Gln711 conformation in (A) Testo --, (B) DHT --, and (C) THG --hARLBD complexes. Electron density maps are contoured at 1[sigma].
 
  The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (2006, 15, 987-999) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22266943 N.M.DeVore, and E.E.Scott (2012).
Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001.
  Nature, 482, 116-119.
PDB codes: 3ruk 3swz
20494939 A.M.Reitzel, and A.M.Tarrant (2010).
Correlated evolution of androgen receptor and aromatase revisited.
  Mol Biol Evol, 27, 2211-2215.  
20436506 H.Wang, J.Li, Y.Gao, Y.Xu, Y.Pan, I.Tsuji, Z.J.Sun, and X.M.Li (2010).
Xeno-oestrogens and phyto-oestrogens are alternative ligands for the androgen receptor.
  Asian J Androl, 12, 535-547.  
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.  
20708648 W.Gao (2010).
Androgen receptor as a therapeutic target.
  Adv Drug Deliv Rev, 62, 1277-1284.  
18815806 M.Schubert, F.Brunet, M.Paris, S.Bertrand, G.Benoit, and V.Laudet (2008).
Nuclear hormone receptor signaling in amphioxus.
  Dev Genes Evol, 218, 651-665.  
  19052375 M.Thauvin, C.Robin-Jagerschmidt, F.Nique, P.Mollat, D.Fleury, and T.Prangé (2008).
Crystallization and preliminary X-ray analysis of the human androgen receptor ligand-binding domain with a coactivator-like peptide and selective androgen receptor modulators.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 1159-1162.  
18799714 S.M.Carroll, J.T.Bridgham, and J.W.Thornton (2008).
Evolution of hormone signaling in elasmobranchs by exploitation of promiscuous receptors.
  Mol Biol Evol, 25, 2643-2652.  
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.

 

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