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- PDB-1p93: CRYSTAL STRUCTURE OF THE AGONIST FORM OF GLUCOCORTICOID RECEPTOR -

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Basic information

Entry
Database: PDB / ID: 1p93
TitleCRYSTAL STRUCTURE OF THE AGONIST FORM OF GLUCOCORTICOID RECEPTOR
Components
  • Glucocorticoid receptor
  • Nuclear receptor coactivator 2
KeywordsHORMONE RECEPTOR / PROTEIN-LIGAND COMPLEX / ANTI PARALLEL ALPHA HELIX SANDWICH
Function / homology
Function and homology information


Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / steroid hormone binding / PTK6 Expression / neuroinflammatory response / glucocorticoid metabolic process / mammary gland duct morphogenesis / microglia differentiation / maternal behavior ...Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / steroid hormone binding / PTK6 Expression / neuroinflammatory response / glucocorticoid metabolic process / mammary gland duct morphogenesis / microglia differentiation / maternal behavior / astrocyte differentiation / motor behavior / cellular response to glucocorticoid stimulus / adrenal gland development / cellular response to steroid hormone stimulus / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / regulation of gluconeogenesis / locomotor rhythm / aryl hydrocarbon receptor binding / regulation of lipid metabolic process / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / estrogen response element binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear receptor-mediated steroid hormone signaling pathway / core promoter sequence-specific DNA binding / Recycling of bile acids and salts / cellular response to hormone stimulus / cellular response to transforming growth factor beta stimulus / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / positive regulation of adipose tissue development / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / steroid binding / Regulation of lipid metabolism by PPARalpha / TBP-class protein binding / regulation of cellular response to insulin stimulus / cellular response to dexamethasone stimulus / BMAL1:CLOCK,NPAS2 activates circadian gene expression / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / synaptic transmission, glutamatergic / response to progesterone / nuclear receptor binding / chromosome segregation / RNA polymerase II transcription regulatory region sequence-specific DNA binding / circadian regulation of gene expression / SUMOylation of intracellular receptors / Heme signaling / mRNA transcription by RNA polymerase II / Hsp90 protein binding / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / DNA-binding transcription repressor activity, RNA polymerase II-specific / positive regulation of miRNA transcription / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / spindle / RNA polymerase II transcription regulator complex / nuclear receptor activity / Regulation of RUNX2 expression and activity / positive regulation of neuron apoptotic process / sequence-specific double-stranded DNA binding / Circadian Clock / chromatin organization / HATs acetylate histones / gene expression / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / transcription regulator complex / Potential therapeutics for SARS / transcription coactivator activity / protein dimerization activity / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear body / nuclear speck / mitochondrial matrix / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein domain specific binding / cell division / negative regulation of DNA-templated transcription / centrosome / chromatin binding / synapse / regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / protein kinase binding / apoptotic process / negative regulation of transcription by RNA polymerase II / signal transduction / positive regulation of transcription by RNA polymerase II
Similarity search - Function
Glucocorticoid receptor / Glucocorticoid receptor / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator ...Glucocorticoid receptor / Glucocorticoid receptor / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain / Nuclear receptor coactivator / Steroid receptor coactivator / Unstructured region on nuclear receptor coactivator protein / PAS domain / : / Nuclear receptor coactivator, interlocking / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / Retinoid X Receptor / Retinoid X Receptor / PAS domain superfamily / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors / Nuclear hormone receptor, ligand-binding domain / Nuclear hormone receptor-like domain superfamily / Ligand-binding domain of nuclear hormone receptor / Nuclear receptor (NR) ligand-binding (LBD) domain profile. / Ligand binding domain of hormone receptors / Zinc finger, NHR/GATA-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
DEXAMETHASONE / Glucocorticoid receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsKauppi, B. / Jakob, C. / Farnegardh, M. / Yang, J. / Ahola, H. / Alarcon, M. / Calles, K. / Engstrom, O. / Harlan, J. / Muchmore, S. ...Kauppi, B. / Jakob, C. / Farnegardh, M. / Yang, J. / Ahola, H. / Alarcon, M. / Calles, K. / Engstrom, O. / Harlan, J. / Muchmore, S. / Ramqvist, A.-K. / Thorell, S. / Ohman, L. / Greer, J. / Gustafsson, J.-A. / Carlstedt-Duke, J. / Carlquist, M.
CitationJournal: J.Biol.Chem. / Year: 2003
Title: 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.
Authors: Kauppi, B. / Jakob, C. / Farnegardh, M. / Yang, J. / Ahola, H. / Alarcon, M. / Calles, K. / Engstrom, O. / Harlan, J. / Muchmore, S. / Ramqvist, A.-K. / Thorell, S. / Ohman, L. / Greer, J. / ...Authors: Kauppi, B. / Jakob, C. / Farnegardh, M. / Yang, J. / Ahola, H. / Alarcon, M. / Calles, K. / Engstrom, O. / Harlan, J. / Muchmore, S. / Ramqvist, A.-K. / Thorell, S. / Ohman, L. / Greer, J. / Gustafsson, J.-A. / Carlstedt-Duke, J. / Carlquist, M.
History
DepositionMay 9, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 8, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jan 31, 2018Group: Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
Revision 1.4Sep 2, 2020Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: struct_biol / struct_keywords ...struct_biol / struct_keywords / struct_ref_seq_dif / struct_site
Item: _struct_keywords.text / _struct_ref_seq_dif.details ..._struct_keywords.text / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Oct 27, 2021Group: Database references / Category: database_2 / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details
Revision 1.6Aug 16, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Remark 300biomolecule Although Nuclear receptors normally funtion as a dimer, the biological unit for this ...biomolecule Although Nuclear receptors normally funtion as a dimer, the biological unit for this receptor is not definitively known.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glucocorticoid receptor
E: Nuclear receptor coactivator 2
B: Glucocorticoid receptor
F: Nuclear receptor coactivator 2
C: Glucocorticoid receptor
G: Nuclear receptor coactivator 2
D: Glucocorticoid receptor
H: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)136,10512
Polymers134,5358
Non-polymers1,5704
Water00
1
A: Glucocorticoid receptor
E: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0263
Polymers33,6342
Non-polymers3921
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1490 Å2
ΔGint-6 kcal/mol
Surface area12510 Å2
MethodPISA
2
B: Glucocorticoid receptor
F: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0263
Polymers33,6342
Non-polymers3921
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1460 Å2
ΔGint-6 kcal/mol
Surface area12100 Å2
MethodPISA
3
C: Glucocorticoid receptor
G: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0263
Polymers33,6342
Non-polymers3921
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1480 Å2
ΔGint-6 kcal/mol
Surface area12340 Å2
MethodPISA
4
D: Glucocorticoid receptor
H: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0263
Polymers33,6342
Non-polymers3921
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1450 Å2
ΔGint-5 kcal/mol
Surface area12320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)127.4, 127.4, 91.8
Angle α, β, γ (deg.)90.0, 90.0, 120.0
Int Tables number144
Space group name H-MP31
DetailsBiological dimer unknown. A-C dimer is composed of the larges contact surface.

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Components

#1: Protein
Glucocorticoid receptor / GR


Mass: 32155.072 Da / Num. of mol.: 4
Fragment: RESIDUE 500-777, hinge and steroid binding domains
Mutation: N517D, F602S, C638D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR3C1 or GRL / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9 / References: UniProt: P04150
#2: Protein/peptide
Nuclear receptor coactivator 2 / NCoA-2 / Transcriptional intermediary factor 2


Mass: 1478.756 Da / Num. of mol.: 4 / Fragment: TIF PEPTIDE 12mer / Source method: obtained synthetically / Details: Synthetized peptide / References: UniProt: Q15596
#3: Chemical
ChemComp-DEX / DEXAMETHASONE / 9A-FLUORO-16BETA-METHYLPREDNISOLONE


Mass: 392.461 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H29FO5 / Comment: medication, antibiotic*YM

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.2 Å3/Da / Density % sol: 61.51 %
Crystal growTemperature: 281 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: PEG 400, MgCl2, Dioxane, Tris, pH 8.5, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.93927 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Feb 21, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.93927 Å / Relative weight: 1
ReflectionResolution: 2.7→55 Å / Num. all: 45763 / Num. obs: 45796 / % possible obs: 100 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3 % / Biso Wilson estimate: 68.3 Å2 / Rmerge(I) obs: 0.103 / Rsym value: 0.085 / Net I/σ(I): 4
Reflection shellResolution: 2.7→2.85 Å / Redundancy: 3 % / Rmerge(I) obs: 0.527 / Mean I/σ(I) obs: 1.7 / Num. unique all: 6724 / Rsym value: 0.429 / % possible all: 100

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Processing

Software
NameVersionClassification
CNX2002refinement
MOSFLMdata reduction
CCP4(SCALA)data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1NHZ

1nhz


Resolution: 2.7→55.17 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 1287422.76 / Data cutoff high rms absF: 1287422.76 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: The structure is merohedrally twinned and it has been refined in CNX2002 with the original structure factors using the least squares residual for hemihedral twinning as a refinement target ...Details: The structure is merohedrally twinned and it has been refined in CNX2002 with the original structure factors using the least squares residual for hemihedral twinning as a refinement target and a twinning factor of 33%. This give a more convincing set of rfactors and also improved the density, R=23.9 Rfree=26.7. The sidechain density of the pepetide is not visible for residues 942-950.
RfactorNum. reflection% reflectionSelection details
Rfree0.363 2233 4.9 %RANDOM
Rwork0.345 ---
all0.35 45796 --
obs0.35 45740 99.9 %-
Solvent computationSolvent model: BABINET / Bsol: 280 Å2
Displacement parametersBiso mean: 61.5 Å2
Baniso -1Baniso -2Baniso -3
1--13.24 Å2-9.16 Å20 Å2
2---13.24 Å20 Å2
3---26.48 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.62 Å0.58 Å
Luzzati d res low-5 Å
Luzzati sigma a0.7 Å0.81 Å
Refinement stepCycle: LAST / Resolution: 2.7→55.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8219 0 112 0 8331
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.012
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d19.6
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.92
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.531.5
X-RAY DIFFRACTIONc_mcangle_it2.32
X-RAY DIFFRACTIONc_scbond_it3.292
X-RAY DIFFRACTIONc_scangle_it3.922.5
LS refinement shellResolution: 2.7→2.87 Å / Rfactor Rfree error: 0.022 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.413 368 4.8 %
Rwork0.451 7303 -
obs--100 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PPROTEIN.TOP
X-RAY DIFFRACTION2LIG.PARLIG.TOP

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