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- PDB-3cld: Ligand binding domain of the glucocorticoid receptor complexed wi... -

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Basic information

Entry
Database: PDB / ID: 3cld
TitleLigand binding domain of the glucocorticoid receptor complexed with fluticazone furoate
Components
  • Glucocorticoid receptor
  • Tif2 coactivator motif
KeywordsTRANSCRIPTION / glucocorticoid receptor / GR / nuclear receptor / Alternative initiation / Chromatin regulator / Disease mutation / DNA-binding / Lipid-binding / Metal-binding / Nucleus / Phosphoprotein / Pseudohermaphroditism / Steroid-binding / Transcription regulation / Zinc-finger
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 / microglia differentiation / mammary gland duct morphogenesis / 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 / microglia differentiation / mammary gland duct morphogenesis / maternal behavior / astrocyte differentiation / cellular response to glucocorticoid stimulus / motor behavior / regulation of gluconeogenesis / adrenal gland development / cellular response to steroid hormone stimulus / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / 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 / regulation of cellular response to insulin stimulus / 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 / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / TBP-class protein binding / steroid binding / Regulation of lipid metabolism by PPARalpha / cellular response to dexamethasone stimulus / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / synaptic transmission, glutamatergic / chromosome segregation / response to progesterone / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / circadian regulation of gene expression / Hsp90 protein binding / Heme signaling / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / 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 / Regulation of RUNX2 expression and activity / nuclear receptor activity / sequence-specific double-stranded DNA binding / positive regulation of neuron apoptotic process / Circadian Clock / chromatin organization / gene expression / HATs acetylate histones / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / transcription regulator complex / Potential therapeutics for SARS / transcription coactivator activity / nuclear body / protein dimerization activity / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear speck / mitochondrial matrix / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / cell division / negative regulation of DNA-templated transcription / centrosome / apoptotic process / synapse / chromatin binding / regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / protein kinase binding / 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 DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / 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
Chem-GW6 / Glucocorticoid receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.84 Å
AuthorsShewchuk, L.M. / McLay, I. / Stewart, E. / Biggadike, K.B. / Hassell, A.M. / Bledsoe, R.K.
CitationJournal: J.Med.Chem. / Year: 2008
Title: X-ray crystal structure of the novel enhanced-affinity glucocorticoid agonist fluticasone furoate in the glucocorticoid receptor-ligand binding domain.
Authors: Biggadike, K. / Bledsoe, R.K. / Hassell, A.M. / Kirk, B.E. / McLay, I.M. / Shewchuk, L.M. / Stewart, E.L.
History
DepositionMar 18, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 24, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / entity / pdbx_entity_nonpoly / struct_ref_seq_dif / struct_site
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glucocorticoid receptor
H: Tif2 coactivator motif
B: Glucocorticoid receptor
C: Tif2 coactivator motif
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,0066
Polymers62,9294
Non-polymers1,0772
Water36020
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3030 Å2
ΔGint-36.1 kcal/mol
Surface area23320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)127.340, 127.340, 77.772
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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Components

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


Mass: 29985.844 Da / Num. of mol.: 2 / Fragment: ligand binding domain, UNP residues 521-777 / Mutation: F602Y, C638G
Source method: isolated from a genetically manipulated source
Details: Protein was expressed as a 6His-GST fusion protein. The 6His-GST portion was cleaved off prior to crystallization with thrombin
Source: (gene. exp.) Homo sapiens (human) / Gene: NR3C1, GRL / Plasmid: pET / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 DE3 / References: UniProt: P04150
#2: Protein/peptide Tif2 coactivator motif


Mass: 1478.756 Da / Num. of mol.: 2 / Source method: obtained synthetically
Details: The peptide was chemically synthesized, the sequence can be found in Homo sapiens (human)
References: UniProt: Q15596*PLUS
#3: Chemical ChemComp-GW6 / (6alpha,11alpha,14beta,16alpha,17alpha)-6,9-difluoro-17-{[(fluoromethyl)sulfanyl]carbonyl}-11-hydroxy-16-methyl-3-oxoan drosta-1,4-dien-17-yl furan-2-carboxylate / Fluticasone furoate


Mass: 538.576 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H29F3O6S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 20 / 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: 2.9 Å3/Da / Density % sol: 57.59 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 100mM BisTrisPropane, 2.2M NaCl, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Dec 10, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.84→110.43 Å / Num. all: 16640 / Num. obs: 15786 / % possible obs: 97.05 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 7.3 % / Rmerge(I) obs: 0.074 / Net I/σ(I): 25
Reflection shellResolution: 2.83→2.91 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.361 / Mean I/σ(I) obs: 2.8 / Num. unique all: 1327 / % possible all: 84.15

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1M2Z

1m2z


Resolution: 2.84→110.43 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.905 / SU B: 33.07 / SU ML: 0.303 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 2 / σ(I): 2 / ESU R Free: 0.396 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26675 850 5.1 %RANDOM
Rwork0.20681 ---
obs0.20984 15786 97.05 %-
all-16640 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 74.392 Å2
Baniso -1Baniso -2Baniso -3
1--3.93 Å2-1.97 Å20 Å2
2---3.93 Å20 Å2
3---5.9 Å2
Refinement stepCycle: LAST / Resolution: 2.84→110.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4002 0 74 20 4096
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0224170
X-RAY DIFFRACTIONr_angle_refined_deg1.1812.0025676
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.3355494
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.98124.251167
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.0115726
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.9441516
X-RAY DIFFRACTIONr_chiral_restr0.070.2662
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.023048
X-RAY DIFFRACTIONr_nbd_refined0.20.21986
X-RAY DIFFRACTIONr_nbtor_refined0.3040.22978
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1170.2111
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1360.236
X-RAY DIFFRACTIONr_mcbond_it0.281.52564
X-RAY DIFFRACTIONr_mcangle_it0.52924022
X-RAY DIFFRACTIONr_scbond_it0.82131835
X-RAY DIFFRACTIONr_scangle_it1.4224.51654
LS refinement shellResolution: 2.838→2.912 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.431 68 -
Rwork0.312 994 -
obs-1327 84.15 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
118.31753.6290.07916.25410.28231.91330.40890.21930.6620.2972-0.23450.5502-0.0048-0.1171-0.1744-0.27460.03550.0011-0.3276-0.053-0.507641.33027.79670.3442
216.9265-2.49860.09785.04621.01131.75720.2869-0.1087-0.4094-0.3544-0.19270.7311-0.1296-0.1449-0.0942-0.2227-0.02830.0577-0.3107-0.0073-0.448242.1142-3.1776-37.2431
323.689411.435420.273621.91082.789520.33740.162.1463-0.8063-0.1010.953-1.21691.2410.1634-1.113-0.05660.0086-0.2745-0.1041-0.32070.623139.4734-11.2507-4.9167
47.2847-9.2472-3.751728.23-6.49329.61410.2861-1.031.43740.07240.7028-0.7246-0.82140.3308-0.9889-0.0842-0.15940.25050.142-0.38330.989438.020315.4808-31.9867
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA528 - 77610 - 258
2X-RAY DIFFRACTION2BC528 - 77610 - 258
3X-RAY DIFFRACTION3HB743 - 7504 - 11
4X-RAY DIFFRACTION4CD743 - 7504 - 11

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