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- PDB-6w9l: Structure of the Ancestral Glucocorticoid Receptor 2 ligand bindi... -

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Basic information

Entry
Database: PDB / ID: 6w9l
TitleStructure of the Ancestral Glucocorticoid Receptor 2 ligand binding domain in complex with deacetylated deflazacort 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 / cellular respiration / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / temperature homeostasis / response to starvation / lncRNA binding / response to muscle activity / intracellular glucose homeostasis / response to dietary excess ...Regulation of MITF-M dependent genes involved in metabolism / positive regulation of fatty acid oxidation / cellular respiration / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / temperature homeostasis / response to starvation / lncRNA binding / response to muscle activity / intracellular glucose homeostasis / response to dietary excess / fatty acid oxidation / energy homeostasis / 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 / digestion / positive regulation of gluconeogenesis / RNA splicing / SUMOylation of transcription cofactors / nuclear receptor binding / gluconeogenesis / respiratory electron transport chain / mitochondrion organization / transcription coregulator activity / transcription initiation at RNA polymerase II promoter / negative regulation of smooth muscle cell proliferation / circadian regulation of gene expression / chromatin DNA binding / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / regulation of circadian rhythm / PML body / Transcriptional regulation of white adipocyte differentiation / Regulation of RUNX2 expression and activity / mRNA processing / : / positive regulation of cold-induced thermogenesis / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / cellular response to oxidative stress / protein-containing complex assembly / neuron apoptotic process / DNA-binding transcription factor binding / sequence-specific DNA binding / negative regulation of neuron apoptotic process / RNA polymerase II-specific DNA-binding transcription factor binding / transcription coactivator activity / protein stabilization / ubiquitin protein ligase binding / positive regulation of gene expression / regulation of DNA-templated transcription / 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
Chem-TUS / 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: 1.45 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)30,5364
Polymers30,0442
Non-polymers4922
Water3,081171
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1280 Å2
ΔGint-13 kcal/mol
Surface area12700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.691, 96.536, 107.460
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-449-

HOH

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Components

#1: Protein Glucocorticoid Receptor / Ancestral Glucocorticoid Receptor2


Mass: 28778.543 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: 1265.627 Da / Num. of mol.: 1 / Fragment: amino acids 141-152 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9UBK2
#3: Chemical ChemComp-TUS / (4aR,4bS,5S,6aS,6bS,9aR,10aS,10bS)-5-hydroxy-6b-(hydroxyacetyl)-4a,6a,8-trimethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]oxazol-2-one


Mass: 399.480 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H29NO5 / Feature type: SUBJECT OF INVESTIGATION
#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.: 171 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Nonpolymer detailsEntity 3 is a deacetylated deflazacort

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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: 60.25 %
Crystal growTemperature: 289.15 K / Method: vapor diffusion, hanging drop
Details: 0.2 M ammonium acetate, 2.5 M sodium formate, and 0.1 M Tris pH 8.5

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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: Mar 5, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.45→34.004 Å / Num. obs: 66358 / % possible obs: 99.7 % / Redundancy: 12 % / Biso Wilson estimate: 22.83 Å2 / CC1/2: 0.971 / CC star: 0.993 / Net I/σ(I): 10.7
Reflection shellResolution: 1.45→1.5 Å / Num. unique obs: 6507 / CC1/2: 0.571

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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: 6NWL

6nwl


Resolution: 1.45→34 Å / SU ML: 0.1607 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.2318
RfactorNum. reflection% reflection
Rfree0.2002 2000 3.02 %
Rwork0.174 --
obs0.1748 66148 99.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 33.41 Å2
Refinement stepCycle: LAST / Resolution: 1.45→34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2105 0 35 171 2311
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01242288
X-RAY DIFFRACTIONf_angle_d1.19393113
X-RAY DIFFRACTIONf_chiral_restr0.0919350
X-RAY DIFFRACTIONf_plane_restr0.0069388
X-RAY DIFFRACTIONf_dihedral_angle_d11.7137316
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.45-1.480.31441340.28474289X-RAY DIFFRACTION94.15
1.48-1.520.25691410.24894532X-RAY DIFFRACTION99.34
1.52-1.570.24751430.22774551X-RAY DIFFRACTION99.58
1.57-1.620.27111410.21234566X-RAY DIFFRACTION99.98
1.62-1.680.21121430.19754584X-RAY DIFFRACTION99.89
1.68-1.740.22611410.18854536X-RAY DIFFRACTION99.96
1.74-1.820.2191430.18864590X-RAY DIFFRACTION99.94
1.82-1.920.21611440.18094588X-RAY DIFFRACTION99.85
1.92-2.040.21041420.17694573X-RAY DIFFRACTION99.75
2.04-2.20.19591430.17514582X-RAY DIFFRACTION99.52
2.2-2.420.20361450.16754642X-RAY DIFFRACTION100
2.42-2.770.22441440.1744614X-RAY DIFFRACTION100
2.77-3.490.1891450.17784675X-RAY DIFFRACTION99.85
3.49-340.17781510.1564826X-RAY DIFFRACTION99.76
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)
15.02476869035-4.69589946565-2.213212688295.081785202920.5963789095936.564475573010.0932655832399-0.3152155646710.257812951133-0.681831495592-0.08436298437190.679085416011-0.0744675810423-0.3805128778950.07161206027680.277167119592-0.00447497041398-0.0471305124420.256780270411-0.03048342151720.316745193509-20.0167872079-14.63740921527.36429986567
23.96709798989-1.206255071141.735358059334.0263270685-4.061271822547.1088044034-0.107781759467-0.673048411991-0.30167217855-0.00261430558469-0.0788573750376-0.3899294451650.4554411169580.0914461799154-0.162211876810.4202964229510.01210286292960.01098610325570.3487200435310.1212099433710.298099632331-1.90002904544-34.604383935919.9783745389
34.59312665536-2.213158778591.776271532552.84086424885-2.030392451362.71114902496-0.0984276165821-0.207176657548-0.399902357370.07590984086630.1278552801850.1808573743130.0662206775106-0.0240803187207-0.07301435388970.222407505589-0.00363159464850.02851923491150.133521771986-0.001939668692950.157161857423-5.01434239259-30.16502778766.20302140986
42.257120575560.2041752258420.9904349222421.66546309071.006540557073.44068048975-0.05781246067710.102363962403-0.129674203433-0.013397118564-0.03369754620490.1008341573530.1768168723290.02610424233510.1148462227530.2348052236790.004217976016420.01211751441830.1624980178310.01617077984240.15155957745-2.74268074594-22.60993669635.98660540698
52.61082206557-2.69009674487-2.763894228833.664742204633.15716210564.14157472428-0.0927172360213-0.558248733618-0.0641128178480.5097669497690.137576437183-0.4019734721180.3241065061810.47310109545-0.09566820497310.4109213546120.0445856169605-0.05422675264080.4100306547620.06667104730750.2252656366.31160779417-26.625340853122.1654982231
61.84946807923-0.1748066565040.06211841434581.365289038010.5343789141632.877216397550.01173833119610.011908576835-0.03234265071670.1289773823180.0153341486337-0.0849023817973-0.05012243271980.240144553297-0.04299562130470.232321116605-0.02816337977220.01078238299790.181853300450.02299080798490.1597710066760.415685262128-16.47589882067.23418324774
74.544183507071.135052097320.9487690113887.413207827095.044919761447.28021239561-0.0543007952838-0.1967078887170.406210621163-0.153417025474-0.1632768455210.396857375542-0.790524181554-0.2763687847650.2609093568190.2624871418320.0117915250385-0.005885486427050.1574310975330.07144930562910.197725623439-10.5591895118-6.299825038692.41490334603
83.2589083508-4.72772375735-0.3890876818965.264517477770.3173538746340.0228782071820.002811274915730.03207318945160.264324030680.0646531446372-0.026263418554-0.437499626832-0.07147942687550.09010454698530.03904080695850.286410491622-0.009412334921250.007551425159180.2110861689610.03290581023210.2171889394385.24177527871-15.52464078315.1295025446
94.72386482848-5.865255302582.302913785089.05096693148-1.838790270693.54579294674-0.32891987937-0.440890646777-1.213785657020.1347580555760.0650758292533-0.5805355268510.4418271462240.2348559587380.2603890854940.3739516623730.04973165412430.06037252741880.237359929580.07350497320650.42761836660110.3056343668-39.8586459486.93214824615
104.763036282365.5754955796-5.921649211448.5979702369-5.876272062958.2840375256-0.2223589345980.440970740939-0.347653694582-0.3807826334840.0530159416159-0.06908988248350.346018311402-0.2023139795440.1134709692640.2788853182630.0396280920050.006261329521740.237181585566-0.01642266641690.2670697891133.94568608797-32.1514197054-2.87694660762
117.36431581134-5.61071285508-7.277694880744.278027721135.712144046547.71920889207-0.1840991293380.138664275220.2457004094420.5174318602670.164083159762-0.3883234408050.2767626377750.4229057865910.03651979770830.2220237776550.00410033138682-0.02322962661410.2697943433010.02544576832040.1506008550315.91652294892-13.0799691299-5.45636380726
121.78228284358-0.618205180817-0.9944321473894.78709600718-5.058806414147.59271926655-0.2363655848670.649792111945-1.094484745030.0508886780243-0.2727818990240.6382744348860.799152840751-0.5182454023590.5406496555610.377656512142-0.07964125408280.002763694108480.27348574723-0.1327552391870.487563501517-11.4771411249-35.2273532664-4.11610296976
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid -2 through 8 )
2X-RAY DIFFRACTION2chain 'A' and (resid 9 through 24 )
3X-RAY DIFFRACTION3chain 'A' and (resid 25 through 57 )
4X-RAY DIFFRACTION4chain 'A' and (resid 58 through 85 )
5X-RAY DIFFRACTION5chain 'A' and (resid 86 through 107 )
6X-RAY DIFFRACTION6chain 'A' and (resid 108 through 151 )
7X-RAY DIFFRACTION7chain 'A' and (resid 152 through 179 )
8X-RAY DIFFRACTION8chain 'A' and (resid 180 through 210 )
9X-RAY DIFFRACTION9chain 'A' and (resid 211 through 219 )
10X-RAY DIFFRACTION10chain 'A' and (resid 220 through 234 )
11X-RAY DIFFRACTION11chain 'A' and (resid 235 through 246 )
12X-RAY DIFFRACTION12chain 'B' and (resid 141 through 152 )

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