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- PDB-3k22: Glucocorticoid Receptor with Bound alaninamide 10 with TIF2 peptide -

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Basic information

Entry
Database: PDB / ID: 3k22
TitleGlucocorticoid Receptor with Bound alaninamide 10 with TIF2 peptide
Components
  • Glucocorticoid receptor
  • Transcriptional Intermediary Factor 2
KeywordsTRANSCRIPTION / Glucocorticoid Receptor / Steroid Hormone Receptor / Nuclear Receptor / GR / glucocorticoids / alpha helical sandwich / meta-channel / Alternative initiation / Chromatin regulator / Disease mutation / DNA-binding / Isopeptide bond / Lipid-binding / Metal-binding / Nucleus / Phosphoprotein / Pseudohermaphroditism / Receptor / 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 / 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 / cellular response to glucocorticoid stimulus / motor behavior / 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 transforming growth factor beta stimulus / cellular response to hormone 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 / 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 / SUMOylation of intracellular receptors / Heme signaling / Hsp90 protein binding / 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 / positive regulation of neuron apoptotic process / nuclear receptor activity / Regulation of RUNX2 expression and activity / 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 / nuclear body / protein dimerization activity / DNA-binding transcription factor activity, RNA polymerase II-specific / 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 / apoptotic process / 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 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
hexyl beta-D-glucopyranoside / Chem-JZS / Glucocorticoid receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsBiggadike, K.B. / McLay, I.M. / Madauss, K.P. / Williams, S.P. / Bledsoe, R.K.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2009
Title: Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor.
Authors: Biggadike, K. / Bledsoe, R.K. / Coe, D.M. / Cooper, T.W. / House, D. / Iannone, M.A. / Macdonald, S.J. / Madauss, K.P. / McLay, I.M. / Shipley, T.J. / Taylor, S.J. / Tran, T.B. / Uings, I.J. ...Authors: Biggadike, K. / Bledsoe, R.K. / Coe, D.M. / Cooper, T.W. / House, D. / Iannone, M.A. / Macdonald, S.J. / Madauss, K.P. / McLay, I.M. / Shipley, T.J. / Taylor, S.J. / Tran, T.B. / Uings, I.J. / Weller, V. / Williams, S.P.
History
DepositionSep 29, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 11, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 25, 2013Group: Derived calculations
Revision 1.3Nov 1, 2017Group: Refinement description / Category: software
Revision 1.4Jul 29, 2020Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations
Category: chem_comp / database_PDB_caveat ...chem_comp / database_PDB_caveat / struct_ref_seq_dif / struct_site / struct_site_gen
Item: _chem_comp.mon_nstd_flag / _chem_comp.type / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.5Oct 13, 2021Group: Database references / Structure summary / Category: chem_comp / database_2 / struct_ref_seq_dif
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details
Revision 1.6Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.7Mar 13, 2024Group: Source and taxonomy / Structure summary / Category: entity / pdbx_entity_src_syn / Item: _entity.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glucocorticoid receptor
H: Transcriptional Intermediary Factor 2
B: Glucocorticoid receptor
D: Transcriptional Intermediary Factor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7579
Polymers62,9294
Non-polymers1,8285
Water79344
1
A: Glucocorticoid receptor
H: Transcriptional Intermediary Factor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2464
Polymers31,4652
Non-polymers7822
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1140 Å2
ΔGint-9 kcal/mol
Surface area12990 Å2
MethodPISA
2
B: Glucocorticoid receptor
D: Transcriptional Intermediary Factor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5115
Polymers31,4652
Non-polymers1,0463
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-10 kcal/mol
Surface area12840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)127.597, 127.597, 78.230
Angle α, β, γ (deg.)90.000, 90.000, 120.000
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 / Mutation: F602Y, C638G
Source method: isolated from a genetically manipulated source
Details: N-terminal 6XHis-GST tag / Source: (gene. exp.) Homo sapiens (human) / Gene: GRL, NR3C1, PGR / Plasmid: pHis GST / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P04150
#2: Protein/peptide Transcriptional Intermediary Factor 2


Mass: 1478.756 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: Purchased / References: UniProt: Q15596*PLUS
#3: Chemical ChemComp-JZS / N-[(1R)-2-amino-1-methyl-2-oxoethyl]-3-(6-methyl-4-{[3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl]amino}-1H-indazol-1-yl)benzamide


Mass: 517.424 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H21F6N5O3 / Details: Medicinal Chemistry
#4: Sugar ChemComp-JZR / hexyl beta-D-glucopyranoside / hexyl beta-D-glucoside / hexyl D-glucoside / hexyl glucoside


Type: D-saccharide / Mass: 264.315 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C12H24O6
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / 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: 2.92 Å3/Da / Density % sol: 57.9 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Dec 15, 2006
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 41085 / % possible obs: 95.2 % / Redundancy: 2 % / Rmerge(I) obs: 0.039 / Χ2: 2.343 / Net I/σ(I): 14.8
Reflection shell
Resolution (Å)Redundancy (%)Num. unique allΧ2Diffraction-ID% possible allRmerge(I) obs
1.8-1.861.8115920.875187.8
1.86-1.941.9128735.876197.80.769
1.94-2.032128281.378197.50.564
2.03-2.132128504.228197.50.423
2.13-2.272129064.991197.60.305
2.27-2.442127711.1091970.11
2.44-2.692127391.264196.80.069
2.69-3.082126181.07196.10.037
3.08-3.882.1125941.258195.10.023
3.88-502.1117161.2491890.017

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.34 Å19.85 Å
Translation2.34 Å19.85 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.005data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→19.85 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.933 / WRfactor Rfree: 0.261 / WRfactor Rwork: 0.216 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.696 / SU B: 16.499 / SU ML: 0.221 / SU R Cruickshank DPI: 0.221 / SU Rfree: 0.192 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.22 / ESU R Free: 0.191 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.255 2889 7 %RANDOM
Rwork0.211 ---
obs0.214 41085 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 99.39 Å2 / Biso mean: 58.659 Å2 / Biso min: 30.91 Å2
Baniso -1Baniso -2Baniso -3
1--4.01 Å2-2.01 Å20 Å2
2---4.01 Å20 Å2
3---6.02 Å2
Refinement stepCycle: LAST / Resolution: 2.1→19.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4182 0 126 44 4352
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0224428
X-RAY DIFFRACTIONr_bond_other_d0.0010.022980
X-RAY DIFFRACTIONr_angle_refined_deg1.1972.0046004
X-RAY DIFFRACTIONr_angle_other_deg1.14837267
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.6755519
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.92223.804184
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.16515771
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.091524
X-RAY DIFFRACTIONr_chiral_restr0.0870.2680
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.024738
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02888
X-RAY DIFFRACTIONr_nbd_refined0.1770.21045
X-RAY DIFFRACTIONr_nbd_other0.1640.22983
X-RAY DIFFRACTIONr_nbtor_refined0.1740.22169
X-RAY DIFFRACTIONr_nbtor_other0.0820.22171
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1280.2206
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1210.29
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1630.247
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1580.28
X-RAY DIFFRACTIONr_mcbond_it0.3481.52700
X-RAY DIFFRACTIONr_mcbond_other0.0531.51048
X-RAY DIFFRACTIONr_mcangle_it0.58324214
X-RAY DIFFRACTIONr_scbond_it0.7432025
X-RAY DIFFRACTIONr_scangle_it1.1264.51790
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.332 200 -
Rwork0.316 2831 -
all-3031 -
obs--100 %
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)
15.72-0.5824-0.93835.05370.04831.2508-0.0861-0.1831-0.7369-0.0025-0.0742-0.49370.0067-0.04340.1603-0.2139-0.03130.0545-0.2275-0.0421-0.2886-24.705834.906217.7335
25.41080.2488-0.78336.7692-1.11081.5253-0.0666-0.1526-0.5541-0.0917-0.0671-0.4154-0.00960.08210.1337-0.27330.00290.0131-0.21260.0719-0.2622-13.629840.281-18.3109
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 1000
2X-RAY DIFFRACTION2B1 - 1000

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