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- PDB-3k23: Glucocorticoid Receptor with Bound D-prolinamide 11 -

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Basic information

Entry
Database: PDB / ID: 3k23
TitleGlucocorticoid Receptor with Bound D-prolinamide 11
Components
  • Glucocorticoid receptor
  • Nuclear receptor coactivator 2
KeywordsTRANSCRIPTION / Glucocorticoid Receptor / Steroid Hormone Receptor / Nuclear Receptor / GR / glucocorticoids / alpha helical sandwich / meta-channel / Alternative initiation / Chromatin regulator / Disease mutation / DNA-binding / Metal-binding / Nucleus / Pseudohermaphroditism / Receptor / Steroid-binding / Transcription regulation / Zinc-finger / Activator
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 / glucocorticoid metabolic process / neuroinflammatory response / microglia differentiation / maternal behavior / mammary gland duct morphogenesis ...Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / steroid hormone binding / PTK6 Expression / glucocorticoid metabolic process / neuroinflammatory response / microglia differentiation / maternal behavior / mammary gland duct morphogenesis / nucleus localization / astrocyte differentiation / cellular response to glucocorticoid stimulus / motor behavior / regulation of gluconeogenesis / adrenal gland development / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / cellular response to steroid hormone stimulus / 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 / intracellular steroid hormone receptor signaling pathway / core promoter sequence-specific DNA binding / Recycling of bile acids and salts / regulation of cellular response to insulin stimulus / cellular response to hormone stimulus / cellular response to transforming growth factor beta stimulus / positive regulation of adipose tissue development / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / TBP-class protein binding / Regulation of lipid metabolism by PPARalpha / steroid binding / cellular response to dexamethasone stimulus / BMAL1:CLOCK,NPAS2 activates circadian gene expression / nuclear receptor coactivator activity / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / response to progesterone / synaptic transmission, glutamatergic / chromosome segregation / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Hsp90 protein binding / circadian regulation of gene expression / 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 / spindle / DNA-binding transcription repressor activity, RNA polymerase II-specific / Transcriptional regulation of white adipocyte differentiation / positive regulation of miRNA transcription / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / positive regulation of neuron apoptotic process / Regulation of RUNX2 expression and activity / nuclear receptor activity / Circadian Clock / sequence-specific double-stranded DNA binding / gene expression / chromatin organization / 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 / protein dimerization activity / nuclear body / DNA-binding transcription factor activity, RNA polymerase II-specific / mitochondrial matrix / nuclear speck / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / cell division / protein domain specific binding / centrosome / negative regulation of DNA-templated transcription / synapse / apoptotic process / chromatin binding / chromatin / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / protein kinase binding / negative regulation of transcription by RNA polymerase II / signal transduction
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 / PAS domain superfamily / Retinoid X Receptor / Retinoid X Receptor / 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-JZN / Glucocorticoid receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3 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 1.0Oct 27, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Oct 13, 2021Group: Database references / Derived calculations / Category: 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
Revision 1.4Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.5Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)96,3619
Polymers94,3946
Non-polymers1,9673
Water84747
1
A: Glucocorticoid receptor
D: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1203
Polymers31,4652
Non-polymers6561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Glucocorticoid receptor
E: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1203
Polymers31,4652
Non-polymers6561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Glucocorticoid receptor
F: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1203
Polymers31,4652
Non-polymers6561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)184.927, 65.956, 71.528
Angle α, β, γ (deg.)90.00, 103.64, 90.00
Int Tables number5
Space group name H-MC121

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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.: 3 / Fragment: UNP residues 521-777, Ligand Binding Domain / 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 / Plasmid: pHis GST / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P04150
#2: Protein/peptide Nuclear receptor coactivator 2 / / NCoA-2 / Transcriptional intermediary factor 2 / hTIF2


Mass: 1478.756 Da / Num. of mol.: 3 / Fragment: UNP residues 740-751 / Source method: obtained synthetically / References: UniProt: Q15596
#3: Chemical ChemComp-JZN / 1-{[3-(4-{[(2R)-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)phenyl]carbonyl}-D-prolinamide


Mass: 655.682 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C34H37F4N5O4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 47 / 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: 2.25 Å3/Da / Density % sol: 45.22 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1M MES 6.5, 28% PEG 5K MME, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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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: 3→50 Å / Num. all: 17141 / Num. obs: 16987 / % possible obs: 99.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.6 % / Biso Wilson estimate: 36.7 Å2 / Rmerge(I) obs: 0.079 / Χ2: 0.93 / Net I/σ(I): 8.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
3-3.112.90.38115650.824193.2
3.11-3.233.40.32616680.754199.3
3.23-3.383.70.24117190.794199.9
3.38-3.563.70.18316921.11199.8
3.56-3.783.70.13217121.115199.8
3.78-4.073.70.08917131.034199.9
4.07-4.483.80.06217070.8321100
4.48-5.133.80.04817280.7951100
5.13-6.463.70.05217260.791100
6.46-503.50.03717571.22199

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Phasing

PhasingMethod: molecular replacement
Phasing MRR rigid body: 0.421 / Cor.coef. Fo:Fc: 0.546 / Cor.coef. Io to Ic: 0.585

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
REFMACrefinement
PDB_EXTRACT3.005data extraction
ADSCQuantumdata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: homology model generated from PR LBD

Resolution: 3→19.82 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.88 / WRfactor Rfree: 0.276 / WRfactor Rwork: 0.21 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.737 / SU B: 44.559 / SU ML: 0.473 / SU R Cruickshank DPI: 0.437 / SU Rfree: 0.572 / TLS residual ADP flag: LIKELY RESIDUAL / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.558 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.289 1170 7 %RANDOM
Rwork0.224 ---
all0.229 16800 --
obs0.229 16800 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 103.22 Å2 / Biso mean: 61.285 Å2 / Biso min: 7.05 Å2
Baniso -1Baniso -2Baniso -3
1-2.12 Å20 Å2-1.8 Å2
2---3.27 Å20 Å2
3---0.3 Å2
Refinement stepCycle: LAST / Resolution: 3→19.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5970 0 141 47 6158
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0226254
X-RAY DIFFRACTIONr_bond_other_d0.0010.024057
X-RAY DIFFRACTIONr_angle_refined_deg1.2432.0018518
X-RAY DIFFRACTIONr_angle_other_deg0.8539916
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3415754
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.14923.771236
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.287151034
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.5441527
X-RAY DIFFRACTIONr_chiral_restr0.0530.2978
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.026900
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021281
X-RAY DIFFRACTIONr_nbd_refined0.2270.21773
X-RAY DIFFRACTIONr_nbd_other0.1860.24333
X-RAY DIFFRACTIONr_nbtor_refined0.1920.23135
X-RAY DIFFRACTIONr_nbtor_other0.0880.23124
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1560.2198
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.1590.22
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2230.228
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1760.250
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1940.26
X-RAY DIFFRACTIONr_mcbond_it0.5791.54960
X-RAY DIFFRACTIONr_mcbond_other0.0491.51529
X-RAY DIFFRACTIONr_mcangle_it0.63826096
X-RAY DIFFRACTIONr_scbond_it0.58932937
X-RAY DIFFRACTIONr_scangle_it0.9154.52422
LS refinement shellResolution: 3→3.076 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.374 91 -
Rwork0.279 1036 -
all-1127 -
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)
12.23550.28750.99513.66110.79781.9840.01350.12420.1431-0.16340.0647-0.0461-0.09620.0823-0.0782-0.12960.015-0.0478-0.2609-0.0583-0.118453.5873-0.37181.8133
21.8454-0.277-0.02430.9218-0.19142.0345-0.0654-0.0758-0.0868-0.1167-0.0237-0.11690.06630.07640.0891-0.15270.00550.0339-0.17970.0145-0.199234.1306-14.5797-28.2925
36.92762.6659-1.86263.7079-1.49242.9131-0.24620.96541.1065-0.15020.43180.23260.3271-0.2022-0.1856-0.3664-0.0829-0.0252-0.07960.2416-0.093324.84717.7927-48.8854
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A525 - 776
2X-RAY DIFFRACTION1D743 - 751
3X-RAY DIFFRACTION1A1
4X-RAY DIFFRACTION2B527 - 700
5X-RAY DIFFRACTION2E742 - 751
6X-RAY DIFFRACTION2B2
7X-RAY DIFFRACTION3C525 - 700
8X-RAY DIFFRACTION3F741 - 750
9X-RAY DIFFRACTION3C3

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