PDBsum entry 1nhz

Go to PDB code: 
protein ligands links
Hormone receptor PDB id
Protein chain
239 a.a. *
HEZ ×3
Waters ×128
* Residue conservation analysis
PDB id:
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)
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
20-Dec-02     Release date:   06-May-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P04150  (GCR_HUMAN) -  Glucocorticoid receptor
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.
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).
Structure of the glucocorticoid receptor, a flexible protein that can adapt to different ligands.
  ChemMedChem, 5, 649-659.  
20949009 D.M.Presman, L.D.Alvarez, V.Levi, S.Eduardo, M.A.Digman, M.A.Martí, A.S.Veleiro, G.Burton, and A.Pecci (2010).
Insights on glucocorticoid receptor activity modulation through the binding of rigid steroids.
  PLoS One, 5, e13279.  
20669259 G.K.Prasanth, L.M.Divya, and C.Sadasivan (2010).
Bisphenol-A can bind to human glucocorticoid receptor as an agonist: an in silico study.
  J Appl Toxicol, 30, 769-774.  
20446002 J.P.Hapgood, and M.Tomasicchio (2010).
Modulation of HIV-1 virulence via the host glucocorticoid receptor: towards further understanding the molecular mechanisms of HIV-1 pathogenesis.
  Arch Virol, 155, 1009-1019.  
19818358 N.C.Nicolaides, Z.Galata, T.Kino, G.P.Chrousos, and E.Charmandari (2010).
The human glucocorticoid receptor: molecular basis of biologic function.
  Steroids, 75, 1.  
20364341 N.Queralt-Rosinach, and J.Mestres (2010).
A canonical cation-π interaction stabilizes the agonist conformation of estrogen-like nuclear receptors.
  Eur Biophys J, 39, 1471-1475.  
20148675 P.Huang, V.Chandra, and F.Rastinejad (2010).
Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics.
  Annu Rev Physiol, 72, 247-272.  
20817759 R.Goyanka, S.Das, H.H.Samuels, and T.Cardozo (2010).
Nuclear receptor engineering based on novel structure activity relationships revealed by farnesyl pyrophosphate.
  Protein Eng Des Sel, 23, 809-815.  
20693691 S.Kakuda, S.Ishizuka, H.Eguchi, M.T.Mizwicki, A.W.Norman, and M.Takimoto-Kamimura (2010).
Structural basis of the histidine-mediated vitamin D receptor agonistic and antagonistic mechanisms of (23S)-25-dehydro-1alpha-hydroxyvitamin D3-26,23-lactone.
  Acta Crystallogr D Biol Crystallogr, 66, 918-926.
PDB codes: 3a2h 3a2i 3a2j
20708648 W.Gao (2010).
Androgen receptor as a therapeutic target.
  Adv Drug Deliv Rev, 62, 1277-1284.  
19067583 C.A.Galea, A.A.High, J.C.Obenauer, A.Mishra, C.G.Park, M.Punta, A.Schlessinger, J.Ma, B.Rost, C.A.Slaughter, and R.W.Kriwacki (2009).
Large-scale analysis of thermostable, mammalian proteins provides insights into the intrinsically disordered proteome.
  J Proteome Res, 8, 211-226.  
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
19375793 K.Ma, M.Hu, Y.Qi, L.Qiu, Y.Jin, J.Yu, and B.Li (2009).
Structure-transfection activity relationships with glucocorticoid-polyethyl-enimine conjugate nuclear gene delivery systems.
  Biomaterials, 30, 3780-3789.  
19666041 R.Kumar, and G.Litwack (2009).
Structural and functional relationships of the steroid hormone receptors' N-terminal transactivation domain.
  Steroids, 74, 877-883.  
19633971 T.Kino, Y.A.Su, and G.P.Chrousos (2009).
Human glucocorticoid receptor isoform beta: recent understanding of its potential implications in physiology and pathophysiology.
  Cell Mol Life Sci, 66, 3435-3448.  
18212811 A.McMaster, and D.W.Ray (2008).
Drug insight: selective agonists and antagonists of the glucocorticoid receptor.
  Nat Clin Pract Endocrinol Metab, 4, 91.  
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.
  J Endocrinol, 197, 205-211.  
18502379 J.Zhang, and D.S.Geller (2008).
Helix 3-helix 5 interactions in steroid hormone receptor function.
  J Steroid Biochem Mol Biol, 109, 279-285.  
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.  
18160712 K.Suino-Powell, Y.Xu, C.Zhang, Y.G.Tao, W.D.Tolbert, S.S.Simons, and H.E.Xu (2008).
Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol.
  Mol Cell Biol, 28, 1915-1923.
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.
  Mol Cell Endocrinol, 295, 59-69.  
17311914 C.E.Bohl, Z.Wu, D.D.Miller, C.E.Bell, and J.T.Dalton (2007).
Crystal structure of the T877A human androgen receptor ligand-binding domain complexed to cyproterone acetate provides insight for ligand-induced conformational changes and structure-based drug design.
  J Biol Chem, 282, 13648-13655.
PDB code: 2oz7
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).
Synthesis of C-11 modified mifepristone analog libraries.
  Mol Divers, 11, 107-111.  
17013809 K.P.Madauss, E.L.Stewart, and S.P.Williams (2007).
The evolution of progesterone receptor ligands.
  Med Res Rev, 27, 374-400.  
20144063 M.L.Mohler, Y.He, Z.Wu, S.S.Hong, and D.D.Miller (2007).
Non-steroidal glucocorticoid receptor antagonists: the race to replace RU-486 for anti-glucocorticoid therapy.
  Expert Opin Ther Pat, 17, 59-81.  
17637966 P.H.Di Chenna, A.S.Veleiro, J.M.Sonego, N.R.Ceballos, M.T.Garland, R.F.Baggio, and G.Burton (2007).
Synthesis of 6,19-cyclopregnanes. Constrained analogues of steroid hormones.
  Org Biomol Chem, 5, 2453-2457.  
17606915 W.H.Bisson, A.V.Cheltsov, N.Bruey-Sedano, B.Lin, J.Chen, N.Goldberger, L.T.May, A.Christopoulos, J.T.Dalton, P.M.Sexton, X.K.Zhang, and R.Abagyan (2007).
Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs.
  Proc Natl Acad Sci U S A, 104, 11927-11932.  
16841235 G.Carta, V.Onnis, A.J.Knox, D.Fayne, and D.G.Lloyd (2006).
Permuting input for more effective sampling of 3D conformer space.
  J Comput Aided Mol Des, 20, 179-190.  
16892386 J.T.Moore, J.L.Collins, and K.H.Pearce (2006).
The nuclear receptor superfamily and drug discovery.
  ChemMedChem, 1, 504-523.  
16839355 K.Oishi, N.Ohkura, and N.Ishida (2006).
Adrenal gland-dependent augmentation of plasminogen activator inhibitor-1 expression in streptozotocin-induced diabetic mice.
  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?
  Expert Opin Investig Drugs, 15, 201-203.  
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.