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PDBsum entry 1nhz

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Hormone receptor PDB id
1nhz
Jmol
Contents
Protein chain
239 a.a. *
Ligands
486
HEZ ×3
Waters ×128
* Residue conservation analysis
PDB id:
1nhz
Name: Hormone receptor
Title: Crystal structure of the antagonist form of glucocorticoid r
Structure: Glucocorticoid receptor. Chain: a. Fragment: residue 500-777, hinge and steroid binding domain synonym: gr. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Biol. unit: Dimer (from PQS)
Resolution:
2.30Å     R-factor:   0.208     R-free:   0.276
Authors: B.Kauppi,C.Jakob,M.Farnegardh,J.Yang,H.Ahola,M.Alarcon,K.Cal O.Engstrom,J.Harlan,S.Muchmore,A.-K.Ramqvist,S.Thorell,L.Oh J.Greer,J.-A.Gustafsson,J.Carlstedt-Duke,M.Carlquist
Key ref:
B.Kauppi et al. (2003). The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism. J Biol Chem, 278, 22748-22754. PubMed id: 12686538 DOI: 10.1074/jbc.M212711200
Date:
20-Dec-02     Release date:   06-May-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P04150  (GCR_HUMAN) -  Glucocorticoid receptor
Seq:
Struc:
 
Seq:
Struc:
777 a.a.
239 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 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.M212711200 J Biol Chem 278:22748-22754 (2003)
PubMed id: 12686538  
 
 
The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism.
B.Kauppi, C.Jakob, M.Färnegårdh, J.Yang, H.Ahola, M.Alarcon, K.Calles, O.Engström, J.Harlan, S.Muchmore, A.K.Ramqvist, S.Thorell, L.Ohman, J.Greer, J.A.Gustafsson, J.Carlstedt-Duke, M.Carlquist.
 
  ABSTRACT  
 
Here we describe the three-dimensional crystal structures of human glucocorticoid receptor ligand-binding domain (GR-LBD) in complex with the antagonist RU-486 at 2.3 A resolution and with the agonist dexamethasone ligand together with a coactivator peptide at 2.8 A. The RU-486 structure was solved in several different crystal forms, two with helix 12 intact (GR1 and GR3) and one with a protease-digested C terminus (GR2). In GR1, part of helix 12 is in a position that covers the co-activator pocket, whereas in the GR3, domain swapping is seen between the crystallographically identical subunits in the GR dimer. An arm consisting of the end of helix 11 and beyond stretches out from one molecule, and helix 12 binds to the other LBD, partly blocking the coactivator pocket of that molecule. This type of GR-LBD dimer has not been described before but might be an artifact from crystallization. Furthermore, the subunits of the GR3 dimers are covalently connected via a disulfide bond between the Cys-736 residues in the two molecules. All three RU-486 GR-LBD structures show that GR has a very flexible region between the end of helix 11 and the end of helix 12.
 
  Selected figure(s)  
 
Figure 1.
FIG. 1. Carved-out SigmaA weighted 2 F[o] - F[c] map at 2.3 and 2.8 Å resolution of antagonist RU-486, GR3 (A) and dexamethasone, GR4 (B), respectively. Most notably, the 17 -hydroxyl group is coordinated by Gln-642 and a water molecule, which in turn hydrogen bonds to the carbonyl oxygen of Cys-736. b, dexamethasone is held in place by hydrogen bonds from surrounding residues. The protein chain is truncated in this picture for better visualization. All pictures were made with PyMOL (43) unless otherwise stated.
Figure 2.
FIG. 2. Schematic drawing of the two GR structures. a, the covalently connected dimer in the GR-LBD and the antagonist RU-486. Helix 12 (yellow) from the blue subunit binds in the hydrophobic groove on the purple subunit, and then the end of the protein (in yellow) chain comes back and binds in the blue subunit. b, in GR4, the four monomers in the asymmetric unit are shown with helix 12 marked in red and the coactivator peptide TIF2 marked in light brown. c and d, two alternative dimer structures.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 22748-22754) copyright 2003.  
  Figures were selected by the author.  

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).
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  PLoS One, 5, e13279.  
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PDB codes: 3a2h 3a2i 3a2j
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The X-ray structure of RU486 bound to the progesterone receptor in a destabilized agonistic conformation.
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PDB code: 2w8y
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18212811 A.McMaster, and D.W.Ray (2008).
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18434350 A.McMaster, T.Chambers, Q.J.Meng, S.Grundy, A.S.Loudon, R.Donn, and D.W.Ray (2008).
Real-time analysis of gene regulation by glucocorticoid hormones.
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18502379 J.Zhang, and D.S.Geller (2008).
Helix 3-helix 5 interactions in steroid hormone receptor function.
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19000019 K.Levitsky, P.Szymanski, F.Jin, J.A.Meurer-Ogden, and R.N.Harkins (2008).
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PDB code: 3bqd
18330543 T.Harada, K.Yamagishi, T.Nakano, K.Kitaura, and H.Tokiwa (2008).
Ab initio fragment molecular orbital study of ligand binding to human progesterone receptor ligand-binding domain.
  Naunyn Schmiedebergs Arch Pharmacol, 377, 607-615.  
18578507 Y.G.Tao, Y.Xu, H.E.Xu, and S.S.Simons (2008).
Mutations of glucocorticoid receptor differentially affect AF2 domain activity in a steroid-selective manner to alter the potency and efficacy of gene induction and repression.
  Biochemistry, 47, 7648-7662.  
18583028 Y.Sun, Y.G.Tao, B.L.Kagan, Y.He, and S.S.Jr (2008).
Modulation of transcription parameters in glucocorticoid receptor-mediated repression.
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17311914 C.E.Bohl, Z.Wu, D.D.Miller, C.E.Bell, and J.T.Dalton (2007).
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  J Biol Chem, 282, 13648-13655.
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17367809 D.Ricketson, U.Hostick, L.Fang, K.R.Yamamoto, and B.D.Darimont (2007).
A conformational switch in the ligand-binding domain regulates the dependence of the glucocorticoid receptor on Hsp90.
  J Mol Biol, 368, 729-741.  
17549597 G.L.Hamilton, and B.J.Backes (2007).
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  Mol Divers, 11, 107-111.  
17013809 K.P.Madauss, E.L.Stewart, and S.P.Williams (2007).
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  Med Res Rev, 27, 374-400.  
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Non-steroidal glucocorticoid receptor antagonists: the race to replace RU-486 for anti-glucocorticoid therapy.
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16839355 K.Oishi, N.Ohkura, and N.Ishida (2006).
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  J Thromb Haemost, 4, 1566-1574.  
17130446 L.Fang, D.Ricketson, L.Getubig, and B.Darimont (2006).
Unliganded and hormone-bound glucocorticoid receptors interact with distinct hydrophobic sites in the Hsp90 C-terminal domain.
  Proc Natl Acad Sci U S A, 103, 18487-18492.  
16600964 L.Frego, and W.Davidson (2006).
Conformational changes of the glucocorticoid receptor ligand binding domain induced by ligand and cofactor binding, and the location of cofactor binding sites determined by hydrogen/deuterium exchange mass spectrometry.
  Protein Sci, 15, 722-730.  
16503757 P.Fuller (2006).
The aldosterone receptor--new insights?
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16390935 R.V.Sionov, O.Cohen, S.Kfir, Y.Zilberman, and E.Yefenof (2006).
Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis.
  J Exp Med, 203, 189-201.  
16823031 Y.Hamuro, S.J.Coales, J.A.Morrow, K.S.Molnar, S.J.Tuske, M.R.Southern, and P.R.Griffin (2006).
Hydrogen/deuterium-exchange (H/D-Ex) of PPARgamma LBD in the presence of various modulators.
  Protein Sci, 15, 1883-1892.  
16129672 C.E.Bohl, D.D.Miller, J.Chen, C.E.Bell, and J.T.Dalton (2005).
Structural basis for accommodation of nonsteroidal ligands in the androgen receptor.
  J Biol Chem, 280, 37747-37754.
PDB codes: 2ax6 2ax7 2ax8 2ax9 2axa
15908963 J.Fagart, J.Huyet, G.M.Pinon, M.Rochel, C.Mayer, and M.E.Rafestin-Oblin (2005).
Crystal structure of a mutant mineralocorticoid receptor responsible for hypertension.
  Nat Struct Mol Biol, 12, 554-555.
PDB codes: 1y9r 1ya3
15883974 J.von Langen, K.H.Fritzemeier, S.Diekmann, and A.Hillisch (2005).
Molecular basis of the interaction specificity between the human glucocorticoid receptor and its endogenous steroid ligand cortisol.
  Chembiochem, 6, 1110-1118.  
15709961 K.W.Nettles, and G.L.Greene (2005).
Ligand control of coregulator recruitment to nuclear receptors.
  Annu Rev Physiol, 67, 309-333.  
15980170 L.Martínez, M.T.Sonoda, P.Webb, J.D.Baxter, M.S.Skaf, and I.Polikarpov (2005).
Molecular dynamics simulations reveal multiple pathways of ligand dissociation from thyroid hormone receptors.
  Biophys J, 89, 2011-2023.  
16922645 S.Ekins, S.Andreyev, A.Ryabov, E.Kirillov, E.A.Rakhmatulin, A.Bugrim, and T.Nikolskaya (2005).
Computational prediction of human drug metabolism.
  Expert Opin Drug Metab Toxicol, 1, 303-324.  
16159155 W.Gao, C.E.Bohl, and J.T.Dalton (2005).
Chemistry and structural biology of androgen receptor.
  Chem Rev, 105, 3352-3370.  
15450240 K.H.Pearce, M.A.Iannone, C.A.Simmons, and J.G.Gray (2004).
Discovery of novel nuclear receptor modulating ligands: an integral role for peptide interaction profiling.
  Drug Discov Today, 9, 741-751.  
15109611 P.J.Fuller (2004).
Aldosterone and DNA: the 50th anniversary.
  Trends Endocrinol Metab, 15, 143-146.  
15350600 P.J.Fuller, B.J.Smith, and F.M.Rogerson (2004).
Cortisol resistance in the New World revisited.
  Trends Endocrinol Metab, 15, 296-299.  
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.