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- PDB-4csj: The discovery of potent selective glucocorticoid receptor modulat... -

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Basic information

Entry
Database: PDB / ID: 4csj
TitleThe discovery of potent selective glucocorticoid receptor modulators, suitable for inhalation
Components
  • GLUCOCORTICOID RECEPTOR
  • NUCLEAR RECEPTOR COACTIVATOR 2
KeywordsSIGNALING PROTEIN / NUCLEAR HORMONE 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 / 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-NN7 / Nuclear receptor coactivator 2 / Glucocorticoid receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsEdman, K. / Ahlgren, R. / Bengtsson, M. / Bladh, H. / Backstrom, S. / Dahmen, J. / Henriksson, K. / Hillertz, P. / Hulikal, V. / Jerre, A. ...Edman, K. / Ahlgren, R. / Bengtsson, M. / Bladh, H. / Backstrom, S. / Dahmen, J. / Henriksson, K. / Hillertz, P. / Hulikal, V. / Jerre, A. / Kinchin, L. / Kase, C. / Lepisto, M. / Mile, I. / Nilsson, S. / Smailagic, A. / Taylor, J. / Tjornebo, A. / Wissler, L. / Hansson, T.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: The Discovery of Potent and Selective Non-Steroidal Glucocorticoid Receptor Modulators, Suitable for Inhalation.
Authors: Edman, K. / Ahlgren, R. / Bengtsson, M. / Bladh, H. / Backstrom, S. / Dahmen, J. / Henriksson, K. / Hillertz, P. / Hulikal, V. / Jerre, A. / Kinchin, L. / Kase, C. / Lepisto, M. / Mile, I. / ...Authors: Edman, K. / Ahlgren, R. / Bengtsson, M. / Bladh, H. / Backstrom, S. / Dahmen, J. / Henriksson, K. / Hillertz, P. / Hulikal, V. / Jerre, A. / Kinchin, L. / Kase, C. / Lepisto, M. / Mile, I. / Nilsson, S. / Smailagic, A. / Taylor, J. / Tjornebo, A. / Wissler, L. / Hansson, T.
History
DepositionMar 7, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 7, 2014Provider: repository / Type: Initial release
Revision 1.1May 21, 2014Group: Database references
Revision 1.2Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GLUCOCORTICOID RECEPTOR
B: NUCLEAR RECEPTOR COACTIVATOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2964
Polymers33,7672
Non-polymers5292
Water1,78399
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1480 Å2
ΔGint-4.6 kcal/mol
Surface area12320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.354, 84.354, 105.669
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: 32187.139 Da / Num. of mol.: 1 / Fragment: LIGAND BINDING DOMAIN, RESIDUES 500-777 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC1 / Production host: TRICHOPLUSIA NI (cabbage looper) / References: UniProt: P04150
#2: Protein/peptide NUCLEAR RECEPTOR COACTIVATOR 2 /


Mass: 1579.752 Da / Num. of mol.: 1 / Fragment: RESIDUES 741-753
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC1 / Production host: TRICHOPLUSIA NI (cabbage looper) / References: UniProt: E7EWM1, UniProt: Q15596*PLUS
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-NN7 / N-[(2S)-1-[[1-(4-fluorophenyl)indazol-4-yl]amino]propan-2-yl]-2,4,6-trimethyl-benzenesulfonamide


Mass: 466.571 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27FN4O2S
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 99 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsPROTEIN INCLUDES STABILISING MUTANTS.

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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: 3.48 Å3/Da / Density % sol: 64.7 % / Description: NONE
Crystal growpH: 7.5
Details: 10% PEG8000, 20% ETHYLENE GLYCOL AND 0.1 M HEPES PH7.5

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Data collection

DiffractionMean temperature: 287 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.98
DetectorType: ADSC CCD / Detector: CCD / Date: Sep 18, 2006 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.3→42.8 Å / Num. obs: 19850 / % possible obs: 99.8 % / Observed criterion σ(I): 1.5 / Redundancy: 4.1 % / Biso Wilson estimate: 49.12 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 4.9
Reflection shellResolution: 2.3→2.36 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.58 / Mean I/σ(I) obs: 1.5 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1M2Z

1m2z


Resolution: 2.3→42.81 Å / Cor.coef. Fo:Fc: 0.9184 / Cor.coef. Fo:Fc free: 0.9131 / SU R Cruickshank DPI: 0.231 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.237 / SU Rfree Blow DPI: 0.183 / SU Rfree Cruickshank DPI: 0.182 / Details: RESIDUES 500-529 ARE DISORDERED
RfactorNum. reflection% reflectionSelection details
Rfree0.2338 1015 5.14 %RANDOM
Rwork0.2185 ---
obs0.2193 19758 99.69 %-
Displacement parametersBiso mean: 52.76 Å2
Baniso -1Baniso -2Baniso -3
1--6.8775 Å20 Å20 Å2
2---6.8775 Å20 Å2
3---13.755 Å2
Refine analyzeLuzzati coordinate error obs: 0.303 Å
Refinement stepCycle: LAST / Resolution: 2.3→42.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2126 0 37 99 2262
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012221HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.023003HARMONIC2
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_planes308HARMONIC5
X-RAY DIFFRACTIONt_it2221HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.67
X-RAY DIFFRACTIONt_other_torsion17.12
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion279SEMIHARMONIC5
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_contact2719SEMIHARMONIC4
LS refinement shellResolution: 2.3→2.42 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.3202 155 5.45 %
Rwork0.2958 2689 -
all0.2971 2844 -
obs--99.69 %

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