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PDBsum entry 3g9p
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protein dna_rna metals Protein-protein interface(s) links
Transcription/DNA PDB id
3g9p

 

 

 

 

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Contents
Protein chains
75 a.a. *
DNA/RNA
Metals
_ZN ×4
Waters ×177
* Residue conservation analysis
PDB id:
3g9p
Name: Transcription/DNA
Title: Gr DNA binding domain:sgk 16bp complex-7
Structure: Glucocorticoid receptor. Chain: b, a. Fragment: unp residues 440-525. Synonym: gr, nuclear receptor subfamily 3 group c member 1. Engineered: yes. DNA (5'-d( Tp Cp Gp Gp Ap Cp Ap Ap Ap Ap Tp Gp Tp Tp Cp T)- 3'). Chain: c. Engineered: yes.
Source: Rattus norvegicus. Brown rat,rat,rats. Organism_taxid: 10116. Gene: nr3c1, grl. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Synthetic: yes
Resolution:
1.65Å     R-factor:   0.178     R-free:   0.203
Authors: M.A.Pufall,K.R.Yamamoto,S.H.Meijsing
Key ref:
S.H.Meijsing et al. (2009). DNA binding site sequence directs glucocorticoid receptor structure and activity. Science, 324, 407-410. PubMed id: 19372434 DOI: 10.1126/science.1164265
Date:
13-Feb-09     Release date:   14-Apr-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P06536  (GCR_RAT) -  Glucocorticoid receptor from Rattus norvegicus
Seq:
Struc: 		 
Seq:
Struc: 		795 a.a.
75 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

DNA/RNA chains
  T-C-G-G-A-C-A-A-A-A-T-G-T-T-C-T 16 bases
  A-A-G-A-A-C-A-T-T-T-T-G-T-C-C-G 16 bases

 

 
DOI no: 10.1126/science.1164265 Science 324:407-410 (2009)
PubMed id: 19372434  
 
 
DNA binding site sequence directs glucocorticoid receptor structure and activity.
S.H.Meijsing, M.A.Pufall, A.Y.So, D.L.Bates, L.Chen, K.R.Yamamoto.
 
  ABSTRACT  
 
Genes are not simply turned on or off, but instead their expression is fine-tuned to meet the needs of a cell. How genes are modulated so precisely is not well understood. The glucocorticoid receptor (GR) regulates target genes by associating with specific DNA binding sites, the sequences of which differ between genes. Traditionally, these binding sites have been viewed only as docking sites. Using structural, biochemical, and cell-based assays, we show that GR binding sequences, differing by as little as a single base pair, differentially affect GR conformation and regulatory activity. We therefore propose that DNA is a sequence-specific allosteric ligand of GR that tailors the activity of the receptor toward specific target genes.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. DNA sequence-mediated structural differences in GR-DBD. (A) Domain structure of GR. [1], tau1. (B) Overlay of chains A and B from GR-DBD:Pal complex shows packed and flipped conformations. (C) Overlay of chain B from GR-DBD complexed with 4-bp spacer (15) (magenta) and 3-bp spacer GBS (green). (D) Composite omit maps of GR-DBD complexed with different GBSs (GilZ, FKBP5, Sgk, and Pal) under the same conditions. Lever arm peptide is shown with 2Fo-Fc (black mesh) and composite omit map (red mesh) overlaid. 		Figure 4.
Fig. 4. Receptor activity is modulated by lever arm residues. (A) H472 is critical for tuning activity. Effects of mutating lever arm residues were assayed using GBS reporters; activities are plotted as percentage of wild type ± SEM (n 3). (B) H472 resides in the DBD pocket formed by the carbonyl adjacent to V468, Y497, and L501. (C) Human DBD sequence alignments reveal variation at V468, Y497, and L501.
 
  The above figures are reprinted from an Open Access publication published by the AAAs: Science (2009, 324, 407-410) copyright 2009.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23222642 W.H.Hudson, C.Youn, and E.A.Ortlund (2013).
The structural basis of direct glucocorticoid-mediated transrepression.
  Nat Struct Mol Biol, 20, 53-58.
PDB codes: 4hn5 4hn6
20398732 A.E.Coutinho, and K.E.Chapman (2011).
The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights.
  Mol Cell Endocrinol, 335, 2.  
21232159 A.S.Arterbery, D.J.Fergus, E.A.Fogarty, J.Mayberry, D.L.Deitcher, W.Lee Kraus, and A.H.Bass (2011).
Evolution of ligand specificity in vertebrate corticosteroid receptors.
  BMC Evol Biol, 11, 14.  
21196123 G.M.Santos, L.Fairall, and J.W.Schwabe (2011).
Negative regulation by nuclear receptors: a plethora of mechanisms.
  Trends Endocrinol Metab, 22, 87-93.  
21190057 J.S.Fraser, and C.J.Jackson (2011).
Mining electron density for functionally relevant protein polysterism in crystal structures.
  Cell Mol Life Sci, 68, 1829-1841.  
21478866 J.Zhang, M.J.Chalmers, K.R.Stayrook, L.L.Burris, Y.Wang, S.A.Busby, B.D.Pascal, R.D.Garcia-Ordonez, J.B.Bruning, M.A.Istrate, D.J.Kojetin, J.A.Dodge, T.P.Burris, and P.R.Griffin (2011).
DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex.
  Nat Struct Mol Biol, 18, 556-563.  
21295369 K.L.MacQuarrie, A.P.Fong, R.H.Morse, and S.J.Tapscott (2011).
Genome-wide transcription factor binding: beyond direct target regulation.
  Trends Genet, 27, 141-148.  
21496643 M.Surjit, K.P.Ganti, A.Mukherji, T.Ye, G.Hua, D.Metzger, M.Li, and P.Chambon (2011).
Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor.
  Cell, 145, 224-241.  
21478865 N.Rochel, F.Ciesielski, J.Godet, E.Moman, M.Roessle, C.Peluso-Iltis, M.Moulin, M.Haertlein, P.Callow, Y.Mély, D.I.Svergun, and D.Moras (2011).
Common architecture of nuclear receptor heterodimers on DNA direct repeat elements with different spacings.
  Nat Struct Mol Biol, 18, 564-570.  
21284984 N.Shimizu, N.Yoshikawa, N.Ito, T.Maruyama, Y.Suzuki, S.Takeda, J.Nakae, Y.Tagata, S.Nishitani, K.Takehana, M.Sano, K.Fukuda, M.Suematsu, C.Morimoto, and H.Tanaka (2011).
Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle.
  Cell Metab, 13, 170-182.  
21039975 S.C.Biddie (2011).
Chromatin architecture and the regulation of nuclear receptor inducible transcription.
  J Neuroendocrinol, 23, 94.  
21383938 S.Willis, and P.R.Griffin (2011).
Mutual information identifies sequence positions conserved within the nuclear receptor superfamily: approach reveals functionally important regions for DNA binding specificity.
  Nucl Recept Signal, 9, e001.  
  20151694 B.Ma, C.J.Tsai, Y.Pan, and R.Nussinov (2010).
Why does binding of proteins to DNA or proteins to proteins not necessarily spell function?
  ACS Chem Biol, 5, 265-272.  
19962400 C.A.Miller, X.Tan, M.Wilson, S.Bhattacharyya, and S.Ludwig (2010).
Single plasmids expressing human steroid hormone receptors and a reporter gene for use in yeast signaling assays.
  Plasmid, 63, 73-78.  
19940143 C.R.Tchen, J.R.Martins, N.Paktiawal, R.Perelli, J.Saklatvala, and A.R.Clark (2010).
Glucocorticoid regulation of mouse and human dual specificity phosphatase 1 (DUSP1) genes: unusual cis-acting elements and unexpected evolutionary divergence.
  J Biol Chem, 285, 2642-2652.  
19575614 F.Holsboer, and M.Ising (2010).
Stress hormone regulation: biological role and translation into therapy.
  Annu Rev Psychol, 61, 81.  
20053725 I.H.Chan, and M.L.Privalsky (2010).
A conserved lysine in the thyroid hormone receptor-alpha1 DNA-binding domain, mutated in hepatocellular carcinoma, serves as a sensor for transcriptional regulation.
  Mol Cancer Res, 8, 15-23.  
20463752 J.Lee, C.A.Myers, N.Williams, M.Abdelaziz, and J.C.Corbo (2010).
Quantitative fine-tuning of photoreceptor cis-regulatory elements through affinity modulation of transcription factor binding sites.
  Gene Ther, 17, 1390-1399.  
20679482 J.R.Flammer, J.Dobrovolna, M.A.Kennedy, Y.Chinenov, C.K.Glass, L.B.Ivashkiv, and I.Rogatsky (2010).
The type I interferon signaling pathway is a target for glucocorticoid inhibition.
  Mol Cell Biol, 30, 4564-4574.  
20174675 J.Simicevic, and B.Deplancke (2010).
DNA-centered approaches to characterize regulatory protein-DNA interaction complexes.
  Mol Biosyst, 6, 462-468.  
20600811 K.De Bosscher, I.M.Beck, and G.Haegeman (2010).
Classic glucocorticoids versus non-steroidal glucocorticoid receptor modulators: survival of the fittest regulator of the immune system?
  Brain Behav Immun, 24, 1035-1042.  
20026583 K.Ohtsuki, K.Kasahara, K.Shirahige, and T.Kokubo (2010).
Genome-wide localization analysis of a complete set of Tafs reveals a specific effect of the taf1 mutation on Taf2 occupancy and provides indirect evidence for different TFIID conformations at different promoters.
  Nucleic Acids Res, 38, 1805-1820.  
21115832 M.A.Kane, A.E.Folias, A.Pingitore, M.Perri, K.M.Obrochta, C.R.Krois, E.Cione, J.Y.Ryu, and J.L.Napoli (2010).
Identification of 9-cis-retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion.
  Proc Natl Acad Sci U S A, 107, 21884-21889.  
20212087 M.K.Kim, Y.S.Kang, H.T.Lai, N.H.Barakat, D.Magante, and W.E.Stumph (2010).
Identification of SNAPc subunit domains that interact with specific nucleotide positions in the U1 and U6 gene promoters.
  Mol Cell Biol, 30, 2411-2423.  
20634803 M.Wiench, and G.L.Hager (2010).
Expanding horizons for nuclear receptors.
  EMBO Rep, 11, 569-571.  
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.  
20508142 R.C.DeKelver, V.M.Choi, E.A.Moehle, D.E.Paschon, D.Hockemeyer, S.H.Meijsing, Y.Sancak, X.Cui, E.J.Steine, J.C.Miller, P.Tam, V.V.Bartsevich, X.Meng, I.Rupniewski, S.M.Gopalan, H.C.Sun, K.J.Pitz, J.M.Rock, L.Zhang, G.D.Davis, E.J.Rebar, I.M.Cheeseman, K.R.Yamamoto, D.M.Sabatini, R.Jaenisch, P.D.Gregory, and F.D.Urnov (2010).
Functional genomics, proteomics, and regulatory DNA analysis in isogenic settings using zinc finger nuclease-driven transgenesis into a safe harbor locus in the human genome.
  Genome Res, 20, 1133-1142.  
20525385 R.Frijters, W.Fleuren, E.J.Toonen, J.P.Tuckermann, H.M.Reichardt, H.van der Maaden, A.van Elsas, M.J.van Lierop, W.Dokter, J.de Vlieg, and W.Alkema (2010).
Prednisolone-induced differential gene expression in mouse liver carrying wild type or a dimerization-defective glucocorticoid receptor.
  BMC Genomics, 11, 359.  
20634319 R.Joshi, L.Sun, and R.Mann (2010).
Dissecting the functional specificities of two Hox proteins.
  Genes Dev, 24, 1533-1545.  
20679481 R.P.Ghosh, R.A.Horowitz-Scherer, T.Nikitina, L.S.Shlyakhtenko, and C.L.Woodcock (2010).
MeCP2 binds cooperatively to its substrate and competes with histone H1 for chromatin binding sites.
  Mol Cell Biol, 30, 4656-4670.  
20334529 R.Rohs, X.Jin, S.M.West, R.Joshi, B.Honig, and R.S.Mann (2010).
Origins of specificity in protein-DNA recognition.
  Annu Rev Biochem, 79, 233-269.  
19703515 S.Connaughton, F.Chowdhury, R.R.Attia, S.Song, Y.Zhang, M.B.Elam, G.A.Cook, and E.A.Park (2010).
Regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) gene expression by glucocorticoids and insulin.
  Mol Cell Endocrinol, 315, 159-167.  
20139418 T.Fauth, F.Müller-Planitz, C.König, T.Straub, and P.B.Becker (2010).
The DNA binding CXC domain of MSL2 is required for faithful targeting the Dosage Compensation Complex to the X chromosome.
  Nucleic Acids Res, 38, 3209-3221.  
20623595 W.H.Raharjo, B.C.Logan, S.Wen, J.M.Kalb, and J.Gaudet (2010).
In vitro and in vivo characterization of Caenorhabditis elegans PHA-4/FoxA response elements.
  Dev Dyn, 239, 2219-2232.  
20074831 Y.Pan, C.J.Tsai, B.Ma, and R.Nussinov (2010).
Mechanisms of transcription factor selectivity.
  Trends Genet, 26, 75-83.  
  20700496 Y.Pan, and R.Nussinov (2010).
Lysine120 interactions with p53 response elements can allosterically direct p53 organization.
  PLoS Comput Biol, 6, 0.  
20132824 Y.Wu, R.Dey, A.Han, N.Jayathilaka, M.Philips, J.Ye, and L.Chen (2010).
Structure of the MADS-box/MEF2 domain of MEF2A bound to DNA and its implication for myocardin recruitment.
  J Mol Biol, 397, 520-533.
PDB code: 3kov
19561066 B.D.Putcha, and E.J.Fernandez (2009).
Direct interdomain interactions can mediate allosterism in the thyroid receptor.
  J Biol Chem, 284, 22517-22524.  
20087432 I.J.McEwan, and A.M.Nardulli (2009).
Nuclear hormone receptor architecture - form and dynamics: The 2009 FASEB Summer Conference on Dynamic Structure of the Nuclear Hormone Receptors.
  Nucl Recept Signal, 7, e011.  
19948487 K.A.Haynes, and P.A.Silver (2009).
Eukaryotic systems broaden the scope of synthetic biology.
  J Cell Biol, 187, 589-596.  
20019798 P.C.Hollenhorst, K.J.Chandler, R.L.Poulsen, W.E.Johnson, N.A.Speck, and B.J.Graves (2009).
DNA specificity determinants associate with distinct transcription factor functions.
  PLoS Genet, 5, e1000778.  
19801529 T.E.Reddy, F.Pauli, R.O.Sprouse, N.F.Neff, K.M.Newberry, M.J.Garabedian, and R.M.Myers (2009).
Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation.
  Genome Res, 19, 2163-2171.  
19888307 Y.Pan, C.J.Tsai, B.Ma, and R.Nussinov (2009).
How do transcription factors select specific binding sites in the genome?
  Nat Struct Mol Biol, 16, 1118-1120.  
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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