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- PDB-6w9k: Structure of the Ancestral Glucocorticoid Receptor 2 ligand bindi... -

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Basic information

Entry
Database: PDB / ID: 6w9k
TitleStructure of the Ancestral Glucocorticoid Receptor 2 ligand binding domain in complex with Prednisolone and PGC1a coregulator fragment
Components
  • Glucocorticoid Receptor
  • Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
KeywordsHORMONE / Glucocorticoid Receptor / anti-inflammation drug
Function / homology
Function and homology information


Regulation of MITF-M dependent genes involved in metabolism / positive regulation of fatty acid oxidation / response to muscle activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / cellular respiration / lncRNA binding / temperature homeostasis / response to starvation / intracellular glucose homeostasis / fatty acid oxidation ...Regulation of MITF-M dependent genes involved in metabolism / positive regulation of fatty acid oxidation / response to muscle activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / cellular respiration / lncRNA binding / temperature homeostasis / response to starvation / intracellular glucose homeostasis / fatty acid oxidation / response to dietary excess / estrogen response element binding / adipose tissue development / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / brown fat cell differentiation / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / nuclear receptor-mediated steroid hormone signaling pathway / energy homeostasis / positive regulation of gluconeogenesis / digestion / respiratory electron transport chain / RNA splicing / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / mitochondrion organization / gluconeogenesis / nuclear receptor binding / transcription initiation at RNA polymerase II promoter / negative regulation of smooth muscle cell proliferation / transcription coregulator activity / circadian regulation of gene expression / Heme signaling / Transcriptional activation of mitochondrial biogenesis / regulation of circadian rhythm / PPARA activates gene expression / PML body / chromatin DNA binding / positive regulation of DNA-binding transcription factor activity / Transcriptional regulation of white adipocyte differentiation / mRNA processing / Regulation of RUNX2 expression and activity / nuclear receptor activity / Circadian Clock / positive regulation of cold-induced thermogenesis / cellular response to oxidative stress / protein-containing complex assembly / DNA-binding transcription factor binding / neuron apoptotic process / negative regulation of neuron apoptotic process / RNA polymerase II-specific DNA-binding transcription factor binding / sequence-specific DNA binding / transcription coactivator activity / protein stabilization / ubiquitin protein ligase binding / regulation of DNA-templated transcription / positive regulation of gene expression / chromatin / positive regulation of DNA-templated transcription / positive regulation of transcription by RNA polymerase II / DNA binding / RNA binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
PGC-1alpha, RNA recognition motif / PGC-1 / : / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / Nuclear hormone receptor / Nuclear hormone receptor, ligand-binding domain ...PGC-1alpha, RNA recognition motif / PGC-1 / : / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / Nuclear hormone receptor / 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 / Nucleotide-binding alpha-beta plait domain superfamily
Similarity search - Domain/homology
prednisolone / Ancestral Glucocorticoid Receptor2 / Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
Similarity search - Component
Biological speciessynthetic construct (others)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsLiu, X. / Ortlund, E.A.
Funding support United States, 2items
OrganizationGrant numberCountry
American Heart Association17POST33660110 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01DK095750 United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2020
Title: Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment.
Authors: Liu, X. / Wang, Y. / Gutierrez, J.S. / Damsker, J.M. / Nagaraju, K. / Hoffman, E.P. / Ortlund, E.A.
History
DepositionMar 23, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 4, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: 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

Downloads & links

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Assembly

Deposited unit
A: Glucocorticoid Receptor
B: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,2524
Polymers29,8002
Non-polymers4532
Water2,486138
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1290 Å2
ΔGint-12 kcal/mol
Surface area12270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.052, 96.089, 108.025
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-447-

HOH

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Components

#1: Protein Glucocorticoid Receptor


Mass: 28702.449 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli) / References: UniProt: A0A1X8XLE9
#2: Protein/peptide Peroxisome proliferator-activated receptor gamma coactivator 1-alpha / PPARGC-1-alpha / Ligand effect modulator 6


Mass: 1097.434 Da / Num. of mol.: 1 / Fragment: amino acids 142-151 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9UBK2
#3: Chemical ChemComp-TUA / prednisolone / Prednisolone / (11alpha)-11,17,21-trihydroxypregna-1,4-diene-3,20-dione


Mass: 360.444 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28O5 / Feature type: SUBJECT OF INVESTIGATION / Comment: hormone*YM
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 138 / 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: 3.09 Å3/Da / Density % sol: 60.24 %
Crystal growTemperature: 289.15 K / Method: vapor diffusion, hanging drop
Details: 0.2 M ammonium acetate, 3.0 M sodium formate, and 0.1 M HEPES 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 17, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→39.25 Å / Num. obs: 48001 / % possible obs: 98.7 % / Redundancy: 12 % / Biso Wilson estimate: 29.1 Å2 / CC1/2: 0.952 / CC star: 0.988 / Net I/σ(I): 13.3
Reflection shellResolution: 1.6→1.66 Å / Num. unique obs: 4531 / CC1/2: 0.765

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3GN8

3gn8


Resolution: 1.6→39.25 Å / SU ML: 0.1752 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.6239
RfactorNum. reflection% reflection
Rfree0.1919 1999 4.16 %
Rwork0.1785 --
obs0.1791 48001 98.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 39.45 Å2
Refinement stepCycle: LAST / Resolution: 1.6→39.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2086 0 32 138 2256
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00692270
X-RAY DIFFRACTIONf_angle_d0.86813086
X-RAY DIFFRACTIONf_chiral_restr0.0596346
X-RAY DIFFRACTIONf_plane_restr0.0044386
X-RAY DIFFRACTIONf_dihedral_angle_d11.6734315
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.640.2871300.26112997X-RAY DIFFRACTION91.62
1.64-1.690.22431440.23453293X-RAY DIFFRACTION99.54
1.69-1.740.26531410.2193271X-RAY DIFFRACTION99.56
1.74-1.790.23021430.2013274X-RAY DIFFRACTION99.36
1.79-1.860.16321430.20113272X-RAY DIFFRACTION99.04
1.86-1.930.19631410.19443262X-RAY DIFFRACTION98.35
1.93-2.020.24111420.19113277X-RAY DIFFRACTION99.8
2.02-2.130.21551460.1893332X-RAY DIFFRACTION100
2.13-2.260.21541430.18363290X-RAY DIFFRACTION100
2.26-2.440.23181440.17813322X-RAY DIFFRACTION99.51
2.44-2.680.21891430.18423303X-RAY DIFFRACTION98.8
2.68-3.070.20021440.18663302X-RAY DIFFRACTION98.57
3.07-3.870.17991470.16763370X-RAY DIFFRACTION99.72
3.87-39.250.16081480.16473437X-RAY DIFFRACTION97.79
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)
17.44332688647-4.367784756953.294265616036.83686792329-3.249692279364.11088780634-0.192403625628-0.898606254909-0.3803388981180.4867694238830.16816803238-0.2121430545880.16214715387-0.109493392734-0.06027880309380.344520372432-0.047572634266-0.03159662315160.4041204473530.1066632674930.325501416885-8.90372823994-26.704914199915.2614977538
21.89639799276-0.3496885882260.5253895745541.48825800896-0.355435070842.036527349290.04008049810130.0324031902393-0.250782224615-0.0480835625427-0.0002031665055030.1364134100970.1732665051260.00479137751375-0.08451361428030.227686628902-0.0152315690480.007498558578690.2143283522420.01835007249420.240223521823-4.44222513347-26.65337434455.90088129744
35.39839495693-4.69447855103-0.9720970446844.788573645161.234701447621.267881710690.04282723747-0.330282796164-0.04438025940360.3294959946650.0110356536339-0.5754753944260.2193405915610.329689810471-0.0487927441570.4353320196420.0143798699757-0.03468632028190.4678925584050.07040488368850.2816362203476.25758607664-26.898496094722.1638241014
42.08934359232-0.2789445543920.2608663689841.89203535716-0.2675464672342.96261893184-0.007259280115780.0590547418093-0.007264615489870.118220330102-0.0182205852082-0.152511729706-0.01335062811230.2208957790730.02582141886810.206039339981-0.02821749095760.00843226248380.2038449680130.02883513054040.2294449409390.371473154578-16.43361845467.47987478365
55.871600403790.3625681555681.364868802636.942162906124.614338026438.07209618868-0.185274793294-0.2367491568310.557424117149-0.01265738247110.01546181875420.275099004127-0.797112513347-0.4160925877250.0353957099920.3014151647340.00749433588387-0.01351594319120.217200375250.1006306001750.327921585801-10.4752716517-6.14754802812.13417949141
65.85565970685-7.53346760651-0.895139676057.572565294711.09208433030.930611667956-0.007561991925660.05197444992460.1824935134090.145357306659-0.0516592796669-0.272790218849-0.07470455907150.1277684956320.02363755889850.214294753416-0.02831447772310.0143583520930.2231386874140.03688986561610.2244841702425.19618147929-15.89215306185.11298823394
77.32526946906-0.439362058548-0.1535221662135.32446154888-2.444685232396.79545025002-0.0366288630740.070201637135-0.685092279178-0.02496324428770.06597222323240.01849814283910.559847595846-0.152656243848-0.05063370465210.2842513793630.03562703384940.00567778199490.179820948163-0.03323290179620.2936889657165.4071454795-35.04342132240.762680342351
87.224364128-5.09791883421-4.192286193443.642217767722.777998022662.891530233140.03168034826170.1291622127980.304789252193-0.1237857236970.194615952269-0.279871770221-0.1632866116590.461327498036-0.2046100962060.245577602922-0.01334055530230.03451461768380.3038765665780.02467584042760.2019836437185.63883710858-12.6880478053-5.45468300669
92.5374374833-0.3181259300411.574852417744.07762892327-0.8041303583372.30203897287-0.1709860171580.200969974502-1.17714193683-0.622337687224-0.03058696131281.564004811870.372109383616-0.6737019138060.3001354945470.510288163194-0.0886881356437-0.1185441386560.372883113353-0.04635331859730.723249930595-11.9150568344-34.8370204469-3.65994771709
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid -2 through 24 )
2X-RAY DIFFRACTION2chain 'A' and (resid 25 through 85 )
3X-RAY DIFFRACTION3chain 'A' and (resid 86 through 107 )
4X-RAY DIFFRACTION4chain 'A' and (resid 108 through 151 )
5X-RAY DIFFRACTION5chain 'A' and (resid 152 through 179 )
6X-RAY DIFFRACTION6chain 'A' and (resid 180 through 210 )
7X-RAY DIFFRACTION7chain 'A' and (resid 211 through 234 )
8X-RAY DIFFRACTION8chain 'A' and (resid 235 through 246 )
9X-RAY DIFFRACTION9chain 'B' and (resid 142 through 151 )

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