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- PDB-4mdd: Crystal Structure of the Glucocorticoid Receptor Bound to a Non-s... -

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Basic information

Entry
Database: PDB / ID: 4mdd
TitleCrystal Structure of the Glucocorticoid Receptor Bound to a Non-steroidal Antagonist Reveals Repositioning and Partial Disordering of Activation Function Helix 12
Components
  • Glucocorticoid receptor
  • Nuclear receptor corepressor 1
KeywordsPROTEIN BINDING / nuclear hormone receptor ligand binding domain
Function / homology
Function and homology information


Regulation of NPAS4 gene transcription / Loss of MECP2 binding ability to the NCoR/SMRT complex / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / steroid hormone binding / PTK6 Expression / glucocorticoid metabolic process / neuroinflammatory response / response to cortisol / mammary gland duct morphogenesis ...Regulation of NPAS4 gene transcription / Loss of MECP2 binding ability to the NCoR/SMRT complex / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / steroid hormone binding / PTK6 Expression / glucocorticoid metabolic process / neuroinflammatory response / response to cortisol / mammary gland duct morphogenesis / negative regulation of androgen receptor signaling pathway / microglia differentiation / astrocyte differentiation / maternal behavior / nuclear thyroid hormone receptor binding / negative regulation of glycolytic process / negative regulation of JNK cascade / regulation of gluconeogenesis / adrenal gland development / cellular response to glucocorticoid stimulus / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / negative regulation of fatty acid metabolic process / cellular response to steroid hormone stimulus / Notch-HLH transcription pathway / locomotor rhythm / histone deacetylase complex / motor behavior / nuclear receptor-mediated steroid hormone signaling pathway / estrogen response element binding / Regulation of MECP2 expression and activity / cellular response to dexamethasone stimulus / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / cellular response to transforming growth factor beta stimulus / Nuclear signaling by ERBB4 / core promoter sequence-specific DNA binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / steroid binding / Regulation of lipid metabolism by PPARalpha / spindle assembly / transcription repressor complex / RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression / Expression of BMAL (ARNTL), CLOCK, and NPAS2 / negative regulation of miRNA transcription / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / TBP-class protein binding / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / SUMOylation of intracellular receptors / HDACs deacetylate histones / Heme signaling / promoter-specific chromatin binding / synaptic transmission, glutamatergic / chromosome segregation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / PPARA activates gene expression / Transcriptional activation of mitochondrial biogenesis / Cytoprotection by HMOX1 / Hsp90 protein binding / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / positive regulation of miRNA transcription / response to wounding / DNA-binding transcription repressor activity, RNA polymerase II-specific / NOTCH1 Intracellular Domain Regulates Transcription / nuclear receptor activity / spindle / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Activation of anterior HOX genes in hindbrain development during early embryogenesis / histone deacetylase binding / HCMV Early Events / sequence-specific double-stranded DNA binding / Regulation of RUNX2 expression and activity / mitotic spindle / transcription corepressor activity / positive regulation of neuron apoptotic process / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / chromatin organization / DNA-binding transcription activator activity, RNA polymerase II-specific / gene expression / Potential therapeutics for SARS / RNA polymerase II-specific DNA-binding transcription factor binding / DNA-binding transcription factor activity, RNA polymerase II-specific / transcription cis-regulatory region binding / nuclear speck / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / mitochondrial matrix / cell division / negative regulation of DNA-templated transcription / apoptotic process / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / centrosome / synapse / protein kinase binding / chromatin / negative regulation of transcription by RNA polymerase II / signal transduction / positive regulation of transcription by RNA polymerase II
Similarity search - Function
N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / Glucocorticoid receptor / Glucocorticoid receptor / SANT domain profile. / SANT domain / Myb domain / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains ...N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / Glucocorticoid receptor / Glucocorticoid receptor / SANT domain profile. / SANT domain / Myb domain / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / : / SANT/Myb domain / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Homeobox-like domain superfamily / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Double treble clef zinc finger, C4 type / 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
Chem-29M / Nuclear receptor corepressor 1 / Glucocorticoid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsCoghlan, M.J. / Luz, J.G.
CitationJournal: To be Published
Title: Crystal Structure of the Glucocorticoid Receptor Bound to a Non-steroidal Antagonist Reveals Repositioning and Partial Disordering of Activation Function Helix 12
Authors: Luz, J.G. / Coghlan, M.J.
History
DepositionAug 22, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 3, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glucocorticoid receptor
B: Glucocorticoid receptor
C: Nuclear receptor corepressor 1
D: Nuclear receptor corepressor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,6186
Polymers62,5984
Non-polymers1,0192
Water2,018112
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7220 Å2
ΔGint-63 kcal/mol
Surface area24070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.543, 72.543, 229.472
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein Glucocorticoid receptor / GR / Nuclear receptor subfamily 3 group C member 1


Mass: 29667.309 Da / Num. of mol.: 2 / Fragment: unp residues 522-777
Mutation: L525S, L528S, L535A, V538T, F602Y, C638D, E684A, E688A, W712S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR3C1, GRL / Production host: Escherichia coli (E. coli) / References: UniProt: P04150
#2: Protein/peptide Nuclear receptor corepressor 1 / N-CoR / N-CoR1


Mass: 1631.937 Da / Num. of mol.: 2 / Fragment: unp residues 2260-2274 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: O75376
#3: Chemical ChemComp-29M / N-[2-{[benzyl(methyl)amino]methyl}-3-(4-fluoro-2-methoxyphenyl)-5-(propan-2-yl)-1H-indol-7-yl]methanesulfonamide


Mass: 509.635 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H32FN3O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 112 / Source method: isolated from a natural source / Formula: H2O

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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: 2.78 Å3/Da / Density % sol: 55.83 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 100mM Tris HCl plus 6% 1,6 - Hexanediol + 24% PEG 8K, pH 7, VAPOR DIFFUSION, SITTING DROP, temperature 294K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97931 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Feb 15, 2012
RadiationMonochromator: Kohzu HLD-4 Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 2.18→19.8 Å / Num. all: 37462 / Num. obs: 406044 / % possible obs: 99.6 % / Biso Wilson estimate: 51.93 Å2
Reflection shellResolution: 2.18→2.3 Å / % possible all: 100

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Processing

Software
NameVersionClassification
AMoREphasing
BUSTER2.11.5refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→19.8 Å / Cor.coef. Fo:Fc: 0.9222 / Cor.coef. Fo:Fc free: 0.8948 / SU R Cruickshank DPI: 0.315 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2584 870 3.09 %RANDOM
Rwork0.2208 ---
obs0.222 28177 99.61 %-
Displacement parametersBiso mean: 54.15 Å2
Baniso -1Baniso -2Baniso -3
1--1.1668 Å20 Å20 Å2
2---1.1668 Å20 Å2
3---2.3337 Å2
Refine analyzeLuzzati coordinate error obs: 0.328 Å
Refinement stepCycle: LAST / Resolution: 2.4→19.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3957 0 72 112 4141
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0094112HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.075560HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1455SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes97HARMONIC2
X-RAY DIFFRACTIONt_gen_planes593HARMONIC5
X-RAY DIFFRACTIONt_it4112HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.76
X-RAY DIFFRACTIONt_other_torsion18.16
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion523SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4822SEMIHARMONIC4
LS refinement shellResolution: 2.4→2.49 Å / Total num. of bins used: 14
RfactorNum. reflection% reflection
Rfree0.2946 86 2.92 %
Rwork0.2361 2856 -
all0.2377 2942 -
obs--99.61 %

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