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- PDB-8vkz: Crystal structure of Glucocorticoid Receptor in complex with an i... -

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Basic information

Entry
Database: PDB / ID: 8vkz
TitleCrystal structure of Glucocorticoid Receptor in complex with an inhibitor
Components
  • Glucocorticoid receptor
  • Nuclear receptor coactivator 2
KeywordsTRANSCRIPTION/INHIBITOR / Glucocorticord Receptor / modulator / TRANSCRIPTION / TRANSCRIPTION-INHIBITOR complex
Function / homology
Function and homology information


Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / steroid hormone binding / glucocorticoid metabolic process / response to cortisol / PTK6 Expression / neuroinflammatory response / mammary gland duct morphogenesis / microglia differentiation ...Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / steroid hormone binding / glucocorticoid metabolic process / response to cortisol / PTK6 Expression / neuroinflammatory response / mammary gland duct morphogenesis / microglia differentiation / maternal behavior / astrocyte differentiation / adrenal gland development / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / regulation of gluconeogenesis / cellular response to glucocorticoid stimulus / cellular response to steroid hormone stimulus / locomotor rhythm / aryl hydrocarbon receptor binding / motor behavior / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / regulation of lipid metabolic process / estrogen response element binding / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / cellular response to dexamethasone stimulus / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear receptor-mediated steroid hormone signaling pathway / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / cellular response to transforming growth factor beta stimulus / core promoter sequence-specific DNA binding / Recycling of bile acids and salts / transcription regulator inhibitor activity / cellular response to hormone stimulus / steroid binding / : / positive regulation of adipose tissue development / Regulation of lipid metabolism by PPARalpha / peroxisome proliferator activated receptor signaling pathway / regulation of cellular response to insulin stimulus / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / response to progesterone / Activation of gene expression by SREBF (SREBP) / 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 / synaptic transmission, glutamatergic / negative regulation of smoothened signaling pathway / SUMOylation of intracellular receptors / chromosome segregation / circadian regulation of gene expression / promoter-specific chromatin binding / mRNA transcription by RNA polymerase II / Heme signaling / Hsp90 protein binding / PPARA activates gene expression / Transcriptional activation of mitochondrial biogenesis / Cytoprotection by HMOX1 / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / response to wounding / positive regulation of miRNA transcription / DNA-binding transcription repressor activity, RNA polymerase II-specific / RNA polymerase II transcription regulator complex / spindle / nuclear receptor activity / sequence-specific double-stranded DNA binding / Regulation of RUNX2 expression and activity / : / positive regulation of neuron apoptotic process / HATs acetylate histones / 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 / transcription regulator complex / gene expression / Estrogen-dependent gene expression / Potential therapeutics for SARS / DNA-binding transcription factor activity, RNA polymerase II-specific / transcription coactivator activity / protein dimerization activity / nuclear speck / nuclear body / RNA polymerase II cis-regulatory region sequence-specific DNA binding / mitochondrial matrix / DNA-binding transcription factor activity / protein domain specific binding / cell division / negative regulation of DNA-templated transcription / apoptotic process / synapse / chromatin binding / centrosome / regulation of DNA-templated transcription / 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 / Nuclear receptor coactivators bHLH domain / 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 / PAS domain superfamily / Nuclear hormone receptor / 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
Similarity search - Domain/homology
Chem-A1ACE / Glucocorticoid receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.133 Å
AuthorsJudge, R.A. / Hobson, A.D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Rsc Med Chem / Year: 2024
Title: Minimising the payload solvent exposed hydrophobic surface area optimises the antibody-drug conjugate properties.
Authors: Hobson, A.D. / Zhu, H. / Qiu, W. / Judge, R.A. / Longenecker, K.
History
DepositionJan 10, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 24, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2May 8, 2024Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)63,1436
Polymers62,0044
Non-polymers1,1392
Water1,74797
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9530 Å2
ΔGint-72 kcal/mol
Surface area22880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.51, 141.65, 47.9
Angle α, β, γ (deg.)90, 93.46, 90
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 29293.021 Da / Num. of mol.: 2 / Mutation: V571M, F602S, C638D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR3C1, GRL / Production host: Escherichia phage Ecwhy_1 (virus) / 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.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-A1ACE / (4aR,4bS,5R,6aS,6bS,8R,9aR,10aR,10bR)-8-{4-[(3-aminophenyl)methyl]phenyl}-5-hydroxy-6b-(hydroxyacetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H,8H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one


Mass: 569.687 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C35H39NO6 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 97 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.1 Å3/Da / Density % sol: 41.52 % / Description: Plates
Crystal growTemperature: 296 K / Method: vapor diffusion / pH: 5.5
Details: 24% (w/v) PEG 400, 200 mM ammonium acetate, 100 mM sodium citrate pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 14, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.133→70.83 Å / Num. obs: 16146 / % possible obs: 89.6 % / Redundancy: 3.4 % / CC1/2: 0.998 / Net I/σ(I): 8.4
Reflection shellResolution: 2.133→2.335 Å / Num. unique obs: 808 / CC1/2: 0.533

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
autoPROCdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.133→70.83 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.906 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 0.313
Details: Note used Staraniso data processing from Global Phasing.
RfactorNum. reflection% reflectionSelection details
Rfree0.2452 802 -RANDOM
Rwork0.187 ---
obs0.19 16146 56.7 %-
Displacement parametersBiso mean: 42.89 Å2
Baniso -1Baniso -2Baniso -3
1-0.5101 Å20 Å2-0.2482 Å2
2--1.97 Å20 Å2
3----2.4801 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: LAST / Resolution: 2.133→70.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4063 0 84 97 4244
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084243HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.95754HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1530SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes721HARMONIC5
X-RAY DIFFRACTIONt_it4243HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion551SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3444SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.49
X-RAY DIFFRACTIONt_other_torsion18.45
LS refinement shellResolution: 2.133→2.27 Å
RfactorNum. reflection% reflection
Rfree0.2299 21 -
Rwork0.2195 --
obs--8.24 %

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