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PDBsum entry 1a28

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Progesterone receptor PDB id
1a28
Jmol
Contents
Protein chain
251 a.a. *
Ligands
STR ×2
Waters ×180
* Residue conservation analysis
PDB id:
1a28
Name: Progesterone receptor
Title: Hormone-bound human progesterone receptor ligand-binding domain
Structure: Progesterone receptor. Chain: a, b. Fragment: ligand binding domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: t47-d. Gene: pgr. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Other_details: breast cancer
Resolution:
1.80Å     R-factor:   0.191     R-free:   0.227
Authors: P.B.Sigler,S.P.Williams
Key ref:
S.P.Williams and P.B.Sigler (1998). Atomic structure of progesterone complexed with its receptor. Nature, 393, 392-396. PubMed id: 9620806 DOI: 10.1038/30775
Date:
19-Jan-98     Release date:   15-Jul-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P06401  (PRGR_HUMAN) -  Progesterone receptor
Seq:
Struc:
 
Seq:
Struc:
933 a.a.
251 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: 10.1038/30775 Nature 393:392-396 (1998)
PubMed id: 9620806  
 
 
Atomic structure of progesterone complexed with its receptor.
S.P.Williams, P.B.Sigler.
 
  ABSTRACT  
 
The physiological effects of progestins are mediated by the progesterone receptor, a member of the steroid/nuclear receptor superfamily. As progesterone is required for maintenance of pregnancy, its receptor has been a target for pharmaceuticals. Here we report the 1.8 A crystal structure of a progesterone-bound ligand-binding domain of the human progesterone receptor. The nature of this structure explains the receptor's selective affinity for progestins and establishes a common mode of recognition of 3-oxy steroids by the cognate receptors. Although the overall fold of the progesterone receptor is similar to that found in related receptors, the progesterone receptor has a quite different mode of dimerization. A hormone-induced stabilization of the carboxy-terminal secondary structure of the ligand-binding domain of the progesterone receptor accounts for the stereochemistry of this distinctive dimer, explains the receptor's characteristic pattern of ligand-dependent protease resistance and its loss of repression, and indicates how the anti-progestin RU486 might work in birth control. The structure also indicates that the analogous 3-keto-steroid receptors may have a similar mechanism of action.
 
  Selected figure(s)  
 
Figure 2.
Figure 2 The progesterone-binding pocket. a, Stereo view of the electron density (sigmaA weighted 2F[o]-F[c] at 1.8 ┼ resolution) of the bound progesterone and surrounding residues contoured at 1.7 superimposed on the refined model. b, space-filling CPK representation of the hormone-binding pocket; carbon, nitrogen and oxygen atoms are grey, blue and red, respectively. Bound progesterone carbon atoms are cyan and oxygen atoms are green. c, Hydrogen-bonding network that serves as the specificity determinant for the 3-oxy function of progesterone. Hydrogen-bond lengths are in ┼. Dashed lines indicate the connectivity of residues 777 and 778. The amido-keto interaction is predicted on the basis of the structure of the ER LBD complexes and sequence homology6. d, Interactions between the PR LBD and bound progesterone (centre). Hydrogen bonds are indicated by solid arrows, and van der Waals contacts (4 ┼ cutoff) by dashed lines.
Figure 3.
Figure 3 Comparison of the PR LBD and RXR LBD dimers. Dashed ends of RXR indicate truncation of the C-terminal five amino acids. Residues in the PR LBD that form the interface are shown at the top. Dashed lines at the top indicate van der Waals contacts (4 ┼ cutoff), and arrows indicate hydrogen bonds. There is also a van der Waals contact between residues Ala 922 and Leu 921.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (1998, 393, 392-396) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

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PDB code: 2w8y
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PDB code: 3bqd
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PDB codes: 2am9 2ama 2amb
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Crystal structure of a mutant mineralocorticoid receptor responsible for hypertension.
  Nat Struct Mol Biol, 12, 554-555.
PDB codes: 1y9r 1ya3
15710879 J.Zhang, J.Simisky, F.T.Tsai, and D.S.Geller (2005).
A critical role of helix 3-helix 5 interaction in steroid hormone receptor function.
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Molecular basis of the interaction specificity between the human glucocorticoid receptor and its endogenous steroid ligand cortisol.
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Selective steroid recognition by a partially bridged resorcin[4]arene cavitand.
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Modelling the interaction of steroid receptors with endocrine disrupting chemicals.
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Molecular modelling of the androgen receptor axis: rational basis for androgen receptor intervention in androgen-independent prostate cancer.
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A ligand-mediated hydrogen bond network required for the activation of the mineralocorticoid receptor.
  J Biol Chem, 280, 31283-31293.
PDB codes: 2aa2 2aa5 2aa6 2aa7 2aax 2ab2
16061183 Y.Li, K.Suino, J.Daugherty, and H.E.Xu (2005).
Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor.
  Mol Cell, 19, 367-380.
PDB code: 2a3i
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Molecular and pharmacological properties of a potent and selective novel nonsteroidal progesterone receptor agonist tanaproget.
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PDB code: 1zuc
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Structure of the murine constitutive androstane receptor complexed to androstenol: a molecular basis for inverse agonism.
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PDB code: 1xnx
14977406 M.L.Privalsky (2004).
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Modelling bound ligands in protein crystal structures.
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15109611 P.J.Fuller (2004).
Aldosterone and DNA: the 50th anniversary.
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Signature of the oligomeric behaviour of nuclear receptors at the sequence and structural level.
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Sumoylation of the progesterone receptor and of the steroid receptor coactivator SRC-1.
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12612084 B.He, and E.M.Wilson (2003).
Electrostatic modulation in steroid receptor recruitment of LXXLL and FXXLF motifs.
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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.
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PDB codes: 1nhz 1p93
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Crystallization of the human glucocorticoid receptor ligand binding domain: a step towards selective glucocorticoids.
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Repressors of androgen and progesterone receptor action.
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Simulation of the different biological activities of diethylstilbestrol (DES) on estrogen receptor alpha and estrogen-related receptor gamma.
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The three-dimensional structure of the liver X receptor beta reveals a flexible ligand-binding pocket that can accommodate fundamentally different ligands.
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PDB codes: 1pq6 1pq9 1pqc
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Molecular origins for the dominant negative function of human glucocorticoid receptor beta.
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Crystal structure of the heterodimeric complex of LXRalpha and RXRbeta ligand-binding domains in a fully agonistic conformation.
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PDB code: 1uhl
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Structure-function relationships of vitamin D including ligand recognition by the vitamin D receptor.
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The binding mode of progesterone to its receptor deduced from molecular dynamics simulations.
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Heat shock protein 90-independent activation of truncated hepadnavirus reverse transcriptase.
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Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids.
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PDB code: 1lv2
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Folding and stability of the ligand-binding domain of the glucocorticoid receptor.
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A point mutation of the AF2 transactivation domain of the glucocorticoid receptor disrupts its interaction with steroid receptor coactivator 1.
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Membrane-bound progesterone receptors contain a cytochrome b5-like ligand-binding domain.
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Binding of ligands and activation of transcription by nuclear receptors.
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Continuous recycling: a mechanism for modulatory signal transduction.
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Participation of critical residues from the extreme C-terminal end of the human androgen receptor in the ligand binding function.
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11157757 C.J.Schwartz, H.M.Sampson, D.Hlousek, A.Percival-Smith, J.W.Copeland, A.J.Simmonds, and H.M.Krause (2001).
FTZ-Factor1 and Fushi tarazu interact via conserved nuclear receptor and coactivator motifs.
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A mineralocorticoid receptor mutation causing human hypertension.
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New variants of inducible Cre recombinase: a novel mutant of Cre-PR fusion protein exhibits enhanced sensitivity and an expanded range of inducibility.
  Nucleic Acids Res, 29, E47.  
11689447 I.Rogatsky, K.A.Zarember, and K.R.Yamamoto (2001).
Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones.
  EMBO J, 20, 6071-6083.  
11154266 J.G.Savory, G.G.Préfontaine, C.Lamprecht, M.Liao, R.F.Walther, Y.A.Lefebvre, and R.J.Haché (2001).
Glucocorticoid receptor homodimers and glucocorticoid-mineralocorticoid receptor heterodimers form in the cytoplasm through alternative dimerization interfaces.
  Mol Cell Biol, 21, 781-793.  
11320241 J.S.Sack, K.F.Kish, C.Wang, R.M.Attar, S.E.Kiefer, Y.An, G.Y.Wu, J.E.Scheffler, M.E.Salvati, S.R.Krystek, R.Weinmann, and H.M.Einspahr (2001).
Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone.
  Proc Natl Acad Sci U S A, 98, 4904-4909.
PDB codes: 1i37 1i38
11331759 J.W.Thornton (2001).
Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions.
  Proc Natl Acad Sci U S A, 98, 5671-5676.  
11744099 M.Schumacher, R.Guennoun, G.Mercier, F.Désarnaud, P.Lacor, J.Bénavides, B.Ferzaz, F.Robert, and E.E.Baulieu (2001).
Progesterone synthesis and myelin formation in peripheral nerves.
  Brain Res Brain Res Rev, 37, 343-359.  
11253922 M.Shimizu, A.Ohno, and S.Yamada (2001).
(10Z)- and (10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3: an improved synthesis via 19-nor-10-oxo-vitamin D.
  Chem Pharm Bull (Tokyo), 49, 312-317.  
11455592 P.Rotkiewicz, W.Sicinska, A.Kolinski, and H.F.DeLuca (2001).
Model of three-dimensional structure of vitamin D receptor and its binding mechanism with 1alpha,25-dihydroxyvitamin D(3).
  Proteins, 44, 188-199.  
11585812 S.Mackem, C.T.Baumann, and G.L.Hager (2001).
A glucocorticoid/retinoic acid receptor chimera that displays cytoplasmic/nuclear translocation in response to retinoic acid. A real time sensing assay for nuclear receptor ligands.
  J Biol Chem, 276, 45501-45504.  
11607933 U.Egner, N.Heinrich, M.Ruff, M.Gangloff, A.Mueller-Fahrnow, and J.M.Wurtz (2001).
Different ligands-different receptor conformations: modeling of the hER alpha LBD in complex with agonists and antagonists.
  Med Res Rev, 21, 523-539.  
11358696 Y.Shi, and J.T.Koh (2001).
Selective regulation of gene expression by an orthogonal estrogen receptor-ligand pair created by polar-group exchange.
  Chem Biol, 8, 501-510.  
11553641 Y.Yamamoto, O.Wada, M.Suzawa, Y.Yogiashi, T.Yano, S.Kato, and J.Yanagisawa (2001).
The tamoxifen-responsive estrogen receptor alpha mutant D351Y shows reduced tamoxifen-dependent interaction with corepressor complexes.
  J Biol Chem, 276, 42684-42691.  
10722692 A.Chauchereau, M.Georgiakaki, M.Perrin-Wolff, E.Milgrom, and H.Loosfelt (2000).
JAB1 interacts with both the progesterone receptor and SRC-1.
  J Biol Chem, 275, 8540-8548.  
10744339 A.J.Oakley, and M.C.Wilce (2000).
Macromolecular crystallography as a tool for investigating drug, enzyme and receptor interactions.
  Clin Exp Pharmacol Physiol, 27, 145-151.  
10760050 C.Hellal-Levy, J.Fagart, A.Souque, and M.E.Rafestin-Oblin (2000).
Mechanistic aspects of mineralocorticoid receptor activation.
  Kidney Int, 57, 1250-1255.  
10734072 D.K.Lee, H.O.Duan, and C.Chang (2000).
From androgen receptor to the general transcription factor TFIIH. Identification of cdk activating kinase (CAK) as an androgen receptor NH(2)-terminal associated coactivator.
  J Biol Chem, 275, 9308-9313.  
10884226 D.S.Geller, A.Farhi, N.Pinkerton, M.Fradley, M.Moritz, A.Spitzer, G.Meinke, F.T.Tsai, P.B.Sigler, and R.P.Lifton (2000).
Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy.
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  10757764 G.E.Carney, and M.Bender (2000).
The Drosophila ecdysone receptor (EcR) gene is required maternally for normal oogenesis.
  Genetics, 154, 1203-1211.  
10757780 I.Tzameli, P.Pissios, E.G.Schuetz, and D.D.Moore (2000).
The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR.
  Mol Cell Biol, 20, 2951-2958.  
  10892801 J.M.Wurtz, B.Guillot, J.Fagart, D.Moras, K.Tietjen, and M.Schindler (2000).
A new model for 20-hydroxyecdysone and dibenzoylhydrazine binding: a homology modeling and docking approach.
  Protein Sci, 9, 1073-1084.  
10845098 J.Zhang, and M.A.Lazar (2000).
The mechanism of action of thyroid hormones.
  Annu Rev Physiol, 62, 439-466.  
10677485 K.Yamamoto, H.Masuno, M.Choi, K.Nakashima, T.Taga, H.Ooizumi, K.Umesono, W.Sicinska, J.VanHooke, H.F.DeLuca, and S.Yamada (2000).
Three-dimensional modeling of and ligand docking to vitamin D receptor ligand binding domain.
  Proc Natl Acad Sci U S A, 97, 1467-1472.  
11250728 M.Ruff, M.Gangloff, J.M.Wurtz, and D.Moras (2000).
Estrogen receptor transcription and transactivation: Structure-function relationship in DNA- and ligand-binding domains of estrogen receptors.
  Breast Cancer Res, 2, 353-359.  
10655475 M.Schapira, B.M.Raaka, H.H.Samuels, and R.Abagyan (2000).
Rational discovery of novel nuclear hormone receptor antagonists.
  Proc Natl Acad Sci U S A, 97, 1008-1013.  
10678179 N.Rochel, J.M.Wurtz, A.Mitschler, B.Klaholz, and D.Moras (2000).
The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand.
  Mol Cell, 5, 173-179.
PDB code: 1db1
11015194 N.Swamy, W.Xu, N.Paz, J.C.Hsieh, M.R.Haussler, G.J.Maalouf, S.C.Mohr, and R.Ray (2000).
Molecular modeling, affinity labeling, and site-directed mutagenesis define the key points of interaction between the ligand-binding domain of the vitamin D nuclear receptor and 1 alpha,25-dihydroxyvitamin D3.
  Biochemistry, 39, 12162-12171.  
10835357 P.F.Egea, A.Mitschler, N.Rochel, M.Ruff, P.Chambon, and D.Moras (2000).
Crystal structure of the human RXRalpha ligand-binding domain bound to its natural ligand: 9-cis retinoic acid.
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PDB code: 1fby
11006480 R.Bursi, and M.B.Groen (2000).
Application of (quantitative) structure-activity relationships to progestagens: from serendipity to structure-based design.
  Eur J Med Chem, 35, 787-796.  
10882139 R.T.Gampe, V.G.Montana, M.H.Lambert, A.B.Miller, R.K.Bledsoe, M.V.Milburn, S.A.Kliewer, T.M.Willson, and H.E.Xu (2000).
Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors.
  Mol Cell, 5, 545-555.
PDB codes: 1fm6 1fm9
10970886 R.T.Gampe, V.G.Montana, M.H.Lambert, G.B.Wisely, M.V.Milburn, and H.E.Xu (2000).
Structural basis for autorepression of retinoid X receptor by tetramer formation and the AF-2 helix.
  Genes Dev, 14, 2229-2241.
PDB codes: 1g1u 1g5y
10867707 S.B.Nagl, S.Das, and T.F.Smith (2000).
Prediction of interaction partners for orphan nuclear receptors by prior-based protein sequence profiles.
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10805730 S.F.Wang, S.Ayer, W.A.Segraves, D.R.Williams, and A.S.Raikhel (2000).
Molecular determinants of differential ligand sensitivities of insect ecdysteroid receptors.
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11050318 W.Bourguet, P.Germain, and H.Gronemeyer (2000).
Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications.
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Allosteric regulation of the discriminative responsiveness of retinoic acid receptor to natural and synthetic ligands by retinoid X receptor and DNA.
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10600690 A.Mueller-Fahrnow, and U.Egner (1999).
Ligand-binding domain of estrogen receptors.
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10412035 A.W.Norman, D.Adams, E.D.Collins, W.H.Okamura, and R.J.Fletterick (1999).
Three-dimensional model of the ligand binding domain of the nuclear receptor for 1alpha,25-dihydroxy-vitamin D(3).
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10601285 B.He, J.A.Kemppainen, J.J.Voegel, H.Gronemeyer, and E.M.Wilson (1999).
Activation function 2 in the human androgen receptor ligand binding domain mediates interdomain communication with the NH(2)-terminal domain.
  J Biol Chem, 274, 37219-37225.  
10410794 C.Wolberger (1999).
Multiprotein-DNA complexes in transcriptional regulation.
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9876133 D.Kosztin, S.Izrailev, and K.Schulten (1999).
Unbinding of retinoic acid from its receptor studied by steered molecular dynamics.
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10318858 D.M.Kraichely, J.J.Collins, R.K.DeLisle, and P.N.MacDonald (1999).
The autonomous transactivation domain in helix H3 of the vitamin D receptor is required for transactivation and coactivator interaction.
  J Biol Chem, 274, 14352-14358.  
10593921 F.M.Rogerson, N.Dimopoulos, P.Sluka, S.Chu, A.J.Curtis, and P.J.Fuller (1999).
Structural determinants of aldosterone binding selectivity in the mineralocorticoid receptor.
  J Biol Chem, 274, 36305-36311.  
  10490591 F.M.Sladek, M.D.Ruse, L.Nepomuceno, S.M.Huang, and M.R.Stallcup (1999).
Modulation of transcriptional activation and coactivator interaction by a splicing variation in the F domain of nuclear receptor hepatocyte nuclear factor 4alpha1.
  Mol Cell Biol, 19, 6509-6522.  
10593951 G.Giannoukos, A.M.Silverstein, W.B.Pratt, and S.S.Simons (1999).
The seven amino acids (547-553) of rat glucocorticoid receptor required for steroid and hsp90 binding contain a functionally independent LXXLL motif that is critical for steroid binding.
  J Biol Chem, 274, 36527-36536.  
10629110 G.K.Whitfield, P.W.Jurutka, C.A.Haussler, and M.R.Haussler (1999).
Steroid hormone receptors: evolution, ligands, and molecular basis of biologic function.
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10198642 H.E.Xu, M.H.Lambert, V.G.Montana, D.J.Parks, S.G.Blanchard, P.J.Brown, D.D.Sternbach, J.M.Lehmann, G.B.Wisely, T.M.Willson, S.A.Kliewer, and M.V.Milburn (1999).
Molecular recognition of fatty acids by peroxisome proliferator-activated receptors.
  Mol Cell, 3, 397-403.
PDB codes: 1gwx 2gwx 3gwx
9920895 H.Hong, B.D.Darimont, H.Ma, L.Yang, K.R.Yamamoto, and M.R.Stallcup (1999).
An additional region of coactivator GRIP1 required for interaction with the hormone-binding domains of a subset of nuclear receptors.
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10500147 H.Ma, and T.M.Penning (1999).
Conversion of mammalian 3alpha-hydroxysteroid dehydrogenase to 20alpha-hydroxysteroid dehydrogenase using loop chimeras: changing specificity from androgens to progestins.
  Proc Natl Acad Sci U S A, 96, 11161-11166.  
  10373553 I.Rogatsky, A.B.Hittelman, D.Pearce, and M.J.Garabedian (1999).
Distinct glucocorticoid receptor transcriptional regulatory surfaces mediate the cytotoxic and cytostatic effects of glucocorticoids.
  Mol Cell Biol, 19, 5036-5049.  
10230636 K.Yamamoto, H.Ooizumi, K.Umesono, A.Verstuyf, R.Bouillon, H.F.DeLuca, T.Shinki, T.Suda, and S.Yamada (1999).
Three-dimensional structure-function relationship of vitamin D: side chain location and various activities.
  Bioorg Med Chem Lett, 9, 1041-1046.  
  10567540 L.A.Sheldon, C.L.Smith, J.E.Bodwell, A.U.Munck, and G.L.Hager (1999).
A ligand binding domain mutation in the mouse glucocorticoid receptor functionally links chromatin remodeling and transcription initiation.
  Mol Cell Biol, 19, 8146-8157.  
9989224 M.Letz, P.Bringmann, M.Mann, A.Mueller-Fahrnow, D.Reipert, P.Scholz, J.M.Wurtz, and U.Egner (1999).
Investigation of the binding interactions of progesterone using muteins of the human progesterone receptor ligand binding domain designed on the basis of a three-dimensional protein model.
  Biochim Biophys Acta, 1429, 391-400.  
  10454556 P.Alen, F.Claessens, G.Verhoeven, W.Rombauts, and B.Peeters (1999).
The androgen receptor amino-terminal domain plays a key role in p160 coactivator-stimulated gene transcription.
  Mol Cell Biol, 19, 6085-6097.  
10591095 R.M.Knegtel, and M.Wagener (1999).
Efficacy and selectivity in flexible database docking.
  Proteins, 37, 334-345.  
10872460 R.V.Weatherman, R.J.Fletterick, and T.S.Scanlan (1999).
Nuclear-receptor ligands and ligand-binding domains.
  Annu Rev Biochem, 68, 559-581.  
9915825 S.H.Hong, and M.L.Privalsky (1999).
Retinoid isomers differ in the ability to induce release of SMRT corepressor from retinoic acid receptor-alpha.
  J Biol Chem, 274, 2885-2892.  
10567404 S.K.Lee, S.L.Anzick, J.E.Choi, L.Bubendorf, X.Y.Guan, Y.K.Jung, O.P.Kallioniemi, J.Kononen, J.M.Trent, D.Azorsa, B.H.Jhun, J.H.Cheong, Y.C.Lee, P.S.Meltzer, and J.W.Lee (1999).
A nuclear factor, ASC-2, as a cancer-amplified transcriptional coactivator essential for ligand-dependent transactivation by nuclear receptors in vivo.
  J Biol Chem, 274, 34283-34293.  
10373460 U.Lind, P.Greenidge, J.A.Gustafsson, A.P.Wright, and J.Carlstedt-Duke (1999).
Valine 571 functions as a regional organizer in programming the glucocorticoid receptor for differential binding of glucocorticoids and mineralocorticoids.
  J Biol Chem, 274, 18515-18523.  
  9808622 B.D.Darimont, R.L.Wagner, J.W.Apriletti, M.R.Stallcup, P.J.Kushner, J.D.Baxter, R.J.Fletterick, and K.R.Yamamoto (1998).
Structure and specificity of nuclear receptor-coactivator interactions.
  Genes Dev, 12, 3343-3356.
PDB code: 1bsx
9813012 J.Uppenberg, C.Svensson, M.Jaki, G.Bertilsson, L.Jendeberg, and A.Berkenstam (1998).
Crystal structure of the ligand binding domain of the human nuclear receptor PPARgamma.
  J Biol Chem, 273, 31108-31112.
PDB code: 3prg
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