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- PDB-6el7: Glucocorticoid Receptor in complex with compound 31 -

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Basic information

Entry
Database: PDB / ID: 6el7
TitleGlucocorticoid Receptor in complex with compound 31
Components
  • Glucocorticoid receptor
  • Nuclear receptor coactivator 2
KeywordsSIGNALING PROTEIN / Glucocorticoid receptor / nuclear hormone receptor / steroid receptor / ligand complex / peptide complex
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
Chem-B9T / Glucocorticoid receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.18 Å
AuthorsEdman, K. / Wissler, L.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile.
Authors: Ripa, L. / Edman, K. / Dearman, M. / Edenro, G. / Hendrickx, R. / Ullah, V. / Chang, H.F. / Lepisto, M. / Chapman, D. / Geschwindner, S. / Wissler, L. / Svanberg, P. / Lawitz, K. / Malmberg, ...Authors: Ripa, L. / Edman, K. / Dearman, M. / Edenro, G. / Hendrickx, R. / Ullah, V. / Chang, H.F. / Lepisto, M. / Chapman, D. / Geschwindner, S. / Wissler, L. / Svanberg, P. / Lawitz, K. / Malmberg, J. / Nikitidis, A. / Olsson, R.I. / Bird, J. / Llinas, A. / Hegelund-Myrback, T. / Berger, M. / Thorne, P. / Harrison, R. / Kohler, C. / Drmota, T.
History
DepositionSep 28, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 21, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 21, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glucocorticoid receptor
B: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2664
Polymers33,7392
Non-polymers5272
Water2,144119
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: Binding of peptide measured by surface plasmon resonance, binding of ligand measured in binding assay
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1520 Å2
ΔGint-3 kcal/mol
Surface area12390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.850, 83.850, 106.120
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: 32029.971 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Expression and crystallisation mutants: N517D, V571M, F602S, C638D, E684A, W712S
Source: (gene. exp.) Homo sapiens (human) / Gene: NR3C1, GRL / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P04150
#2: Protein/peptide Nuclear receptor coactivator 2 / NCoA-2 / Class E basic helix-loop-helix protein 75 / bHLHe75 / Transcriptional intermediary factor 2 / hTIF2


Mass: 1708.931 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: NCoA2 peptide / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-B9T / ~{N}-[(1~{R},2~{S})-1-(2-bromanyl-4-cyano-phenoxy)-1-(2-cyclopropylpyrimidin-5-yl)propan-2-yl]-2,2-bis(fluoranyl)propanamide


Mass: 465.291 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19BrF2N4O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 119 / 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: 3.19 Å3/Da / Density % sol: 61.47 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 8-10% PEG8000, 10-19% Ethylene Glycol, 0.1 M HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.972 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 15, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.972 Å / Relative weight: 1
ReflectionResolution: 2.18→59.93 Å / Num. obs: 22993 / % possible obs: 99.8 % / Redundancy: 6.1 % / Biso Wilson estimate: 47.93 Å2 / Rpim(I) all: 0.057 / Net I/σ(I): 18.1
Reflection shellResolution: 2.18→2.24 Å / Mean I/σ(I) obs: 2.5 / Rpim(I) all: 0.701

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4csj

4csj


Resolution: 2.18→59.93 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.169 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.174 / SU Rfree Blow DPI: 0.155 / SU Rfree Cruickshank DPI: 0.154
RfactorNum. reflection% reflectionSelection details
Rfree0.225 1178 5.13 %RANDOM
Rwork0.192 ---
obs0.194 22968 99.7 %-
Displacement parametersBiso mean: 52.01 Å2
Baniso -1Baniso -2Baniso -3
1--3.5991 Å20 Å20 Å2
2---3.5991 Å20 Å2
3---7.1981 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: 1 / Resolution: 2.18→59.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2115 0 33 119 2267
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0112198HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.012971HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d787SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes57HARMONIC2
X-RAY DIFFRACTIONt_gen_planes311HARMONIC5
X-RAY DIFFRACTIONt_it2198HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.77
X-RAY DIFFRACTIONt_other_torsion15.67
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion280SEMIHARMONIC5
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_contact2618SEMIHARMONIC4
LS refinement shellResolution: 2.18→2.28 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2453 146 5.29 %
Rwork0.204 2615 -
all0.2061 2761 -
obs--99.42 %
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)
11.93860.05571.08951.3065-0.13042.3827-0.0853-0.09760.1717-0.0393-0.02550.177-0.2339-0.30520.1108-0.08270.0652-0.0082-0.0825-0.0342-0.0862-34.1771-11.74983.186
29.4297-1.7503-2.35.3743-1.65023.0576-0.0740.16810.0914-0.02910.0578-0.1947-0.02080.20050.0162-0.03210.05140.0238-0.0117-0.0401-0.0037-15.7338-18.7491-1.6132
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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