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- PDB-5g3j: Discovery of New Selective Glucocorticoid Receptor Agonist Leads -

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Basic information

Entry
Database: PDB / ID: 5g3j
TitleDiscovery of New Selective Glucocorticoid Receptor Agonist Leads
Components
  • GLUCOCORTICOID RECEPTOR
  • NUCLEAR RECEPTOR COACTIVATOR 2
KeywordsDNA BINDING PROTEIN / GLUCOCORTICOID RECEPTOR / NUCLEAR HORMONE RECEPTOR / STEROID RECEPTOR / SIGNALING PROTEIN / 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 / microglia differentiation / mammary gland duct morphogenesis / 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 / microglia differentiation / mammary gland duct morphogenesis / maternal behavior / astrocyte differentiation / cellular response to glucocorticoid stimulus / motor behavior / regulation of gluconeogenesis / adrenal gland development / cellular response to steroid hormone stimulus / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / 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 / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / estrogen response element binding / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear receptor-mediated steroid hormone signaling pathway / core promoter sequence-specific DNA binding / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / 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 / steroid binding / Regulation of lipid metabolism by PPARalpha / 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 / 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 / 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 / Regulation of RUNX2 expression and activity / nuclear receptor activity / sequence-specific double-stranded DNA binding / positive regulation of neuron apoptotic process / Circadian Clock / chromatin organization / gene expression / 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 / nuclear body / protein dimerization activity / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear speck / mitochondrial matrix / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / cell division / negative regulation of DNA-templated transcription / centrosome / apoptotic process / synapse / chromatin binding / regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / 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 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-E7T / Glucocorticoid receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsBerger, M. / Edman, K. / Wissler, L. / Neuhaus, R. / Rehwinkel, H. / Schacke, H. / Jaroch, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2017
Title: Discovery of New Selective Glucocorticoid Receptor Agonist Leads.
Authors: Berger, M. / Rehwinkel, H. / Schmees, N. / Schacke, H. / Edman, K. / Wissler, L. / Reichel, A. / Jaroch, S.
History
DepositionApr 27, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 15, 2017Provider: repository / Type: Initial release
Revision 1.1Aug 23, 2017Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.type
Revision 1.2Apr 3, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 1.3Jan 10, 2024Group: 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)35,0275
Polymers33,8962
Non-polymers1,1313
Water1,31573
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2450 Å2
ΔGint-6.4 kcal/mol
Surface area13200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.263, 84.263, 106.678
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#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 / Cell line (production host): High Five / 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 ...NCOA-2 / CLASS E BASIC HELIX-LOOP-HELIX PROTEIN 75 / BHLHE75 / TRANSCRIPTIONAL INTERMEDIARY FACTOR 2 / HTIF2 / NCOA2


Mass: 1708.931 Da / Num. of mol.: 1 / Fragment: RESIDUES 740-753 / Source method: obtained synthetically / Source: (synth.) HOMO SAPIENS (human) / References: UniProt: Q15596

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Non-polymers , 4 types, 76 molecules

#3: Chemical ChemComp-CPS / 3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE / CHAPS


Mass: 614.877 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H58N2O7S / Comment: detergent*YM
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-E7T / 5-[[(1S,2R,4R)-4-ethyl-6,7-bis(fluoranyl)-2,5-bis(oxidanyl)-2-(trifluoromethyl)-3,4-dihydro-1H-naphthalen-1-yl]amino]-1H-quinolin-2-one


Mass: 454.390 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H19F5N2O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 73 / 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: 3.39 Å3/Da / Density % sol: 63.7 % / Description: NONE
Crystal growpH: 7.5
Details: 8% PEG8000, 15% ETHYLENE GLYCOL AND 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: 0.98
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 26, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.4→43.1 Å / Num. obs: 17005 / % possible obs: 97.4 % / Observed criterion σ(I): 2 / Redundancy: 4.8 % / Biso Wilson estimate: 48.98 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 7.1
Reflection shellResolution: 2.4→2.46 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.4 / Mean I/σ(I) obs: 1.8 / % possible all: 97.4

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4CSJ

4csj


Resolution: 2.4→43.06 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.915 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.256 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.261 / SU Rfree Blow DPI: 0.208 / SU Rfree Cruickshank DPI: 0.208
RfactorNum. reflection% reflectionSelection details
Rfree0.235 858 5.05 %RANDOM
Rwork0.197 ---
obs0.198 17005 96.5 %-
Displacement parametersBiso mean: 52.11 Å2
Baniso -1Baniso -2Baniso -3
1--5.1973 Å20 Å20 Å2
2---5.1973 Å20 Å2
3---10.3947 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: LAST / Resolution: 2.4→43.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2134 0 72 73 2279
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012255HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.023062HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d810SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes58HARMONIC2
X-RAY DIFFRACTIONt_gen_planes309HARMONIC5
X-RAY DIFFRACTIONt_it2255HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.53
X-RAY DIFFRACTIONt_other_torsion16.58
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion293SEMIHARMONIC5
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_contact2667SEMIHARMONIC4
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)
11.58420.45311.00541.8440.98342.5244-0.0112-0.0610.010.0611-0.15710.24960.1704-0.4790.1683-0.1599-0.04340.0417-0.0477-0.0348-0.1582-7.0943-35.442-14.4833
25.35281.3451-0.60835.2606-3.40281.4803-0.00990.04840.0613-0.07290.04630.0274-0.09250.0465-0.0364-0.0665-0.06220.04910.01320.01490.01478.4534-23.2643-19.4218
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A
2X-RAY DIFFRACTION2CHAIN B

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