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- PDB-7prx: wildtype ligand binding domain of the glucocorticoid receptor com... -

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Basic information

Entry
Database: PDB / ID: 7prx
Titlewildtype ligand binding domain of the glucocorticoid receptor complexed with velsecorat and a PGC1a coactivator fragment
Components
  • Glucocorticoid receptor
  • Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
KeywordsSIGNALING PROTEIN / nuclear receptor / ligand-activated transcription factor / agonist
Function / homology
Function and homology information


Regulation of MITF-M dependent genes involved in metabolism / Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / response to cortisol / steroid hormone binding / glucocorticoid metabolic process / PTK6 Expression / neuroinflammatory response / positive regulation of fatty acid oxidation ...Regulation of MITF-M dependent genes involved in metabolism / Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / response to cortisol / steroid hormone binding / glucocorticoid metabolic process / PTK6 Expression / neuroinflammatory response / positive regulation of fatty acid oxidation / mammary gland duct morphogenesis / microglia differentiation / cellular respiration / astrocyte differentiation / maternal behavior / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / cellular response to glucocorticoid stimulus / motor behavior / regulation of gluconeogenesis / adrenal gland development / cellular response to steroid hormone stimulus / temperature homeostasis / lncRNA binding / response to muscle activity / response to starvation / intracellular glucose homeostasis / fatty acid oxidation / response to dietary excess / estrogen response element binding / adipose tissue development / nuclear receptor-mediated steroid hormone signaling pathway / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / brown fat cell differentiation / core promoter sequence-specific DNA binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / energy homeostasis / cellular response to transforming growth factor beta stimulus / digestion / steroid binding / TBP-class protein binding / positive regulation of gluconeogenesis / cellular response to dexamethasone stimulus / RNA splicing / SUMOylation of transcription cofactors / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / positive regulation of DNA-binding transcription factor activity / nuclear receptor binding / respiratory electron transport chain / gluconeogenesis / RNA polymerase II transcription regulatory region sequence-specific DNA binding / synaptic transmission, glutamatergic / mitochondrion organization / chromosome segregation / transcription coregulator activity / transcription initiation at RNA polymerase II promoter / SUMOylation of intracellular receptors / negative regulation of smooth muscle cell proliferation / promoter-specific chromatin binding / Hsp90 protein binding / circadian regulation of gene expression / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / regulation of circadian rhythm / PML body / Nuclear Receptor transcription pathway / chromatin DNA binding / Transcriptional regulation of white adipocyte differentiation / positive regulation of miRNA transcription / response to wounding / DNA-binding transcription repressor activity, RNA polymerase II-specific / spindle / nuclear receptor activity / mRNA processing / Regulation of RUNX2 expression and activity / sequence-specific double-stranded DNA binding / positive regulation of neuron apoptotic process / : / chromatin organization / positive regulation of cold-induced thermogenesis / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / DNA-binding transcription activator activity, RNA polymerase II-specific / cellular response to oxidative stress / protein-containing complex assembly / neuron apoptotic process / gene expression / DNA-binding transcription factor binding / negative regulation of neuron apoptotic process / RNA polymerase II-specific DNA-binding transcription factor binding / sequence-specific DNA binding / Potential therapeutics for SARS / transcription coactivator activity / DNA-binding transcription factor activity, RNA polymerase II-specific / protein stabilization / nuclear speck / mitochondrial matrix / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / cell division / negative regulation of DNA-templated transcription
Similarity search - Function
PGC-1alpha, RNA recognition motif / PGC-1 / Glucocorticoid receptor / Glucocorticoid receptor / : / Retinoid X Receptor / Retinoid X Receptor / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. ...PGC-1alpha, RNA recognition motif / PGC-1 / Glucocorticoid receptor / Glucocorticoid receptor / : / Retinoid X Receptor / Retinoid X Receptor / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding 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 / Nucleotide-binding alpha-beta plait domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Velsecorat / Glucocorticoid receptor / Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsEdman, K. / Wissler, L. / Koehler, C. / Postel, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat.Struct.Mol.Biol. / Year: 2023
Title: Quaternary glucocorticoid receptor structure highlights allosteric interdomain communication.
Authors: Postel, S. / Wissler, L. / Johansson, C.A. / Gunnarsson, A. / Gordon, E. / Collins, B. / Castaldo, M. / Kohler, C. / Oling, D. / Johansson, P. / Froderberg Roth, L. / Beinsteiner, B. / ...Authors: Postel, S. / Wissler, L. / Johansson, C.A. / Gunnarsson, A. / Gordon, E. / Collins, B. / Castaldo, M. / Kohler, C. / Oling, D. / Johansson, P. / Froderberg Roth, L. / Beinsteiner, B. / Dainty, I. / Delaney, S. / Klaholz, B.P. / Billas, I.M.L. / Edman, K.
History
DepositionSep 22, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 8, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 15, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Mar 29, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)31,9773
Polymers31,3702
Non-polymers6071
Water82946
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-11 kcal/mol
Surface area13070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.342, 73.433, 43.933
Angle α, β, γ (deg.)90, 105.86, 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: 29108.875 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR3C1, GRL / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P04150
#2: Protein/peptide Peroxisome proliferator-activated receptor gamma coactivator 1-alpha / PGC-1-alpha / PPAR-gamma coactivator 1-alpha / PPARGC-1-alpha / Ligand effect modulator 6 / PGC1a ...PGC-1-alpha / PPAR-gamma coactivator 1-alpha / PPARGC-1-alpha / Ligand effect modulator 6 / PGC1a coactivator fragment


Mass: 2261.611 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9UBK2
#3: Chemical ChemComp-82H / Velsecorat / 3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-[(3R)-oxolan-3-yl]benzamide / 3-[5-[(1R,2S)-2-[2,2-bis(fluoranyl)propanoylamino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-[(3R)-oxolan-3-yl]benzamide


Mass: 606.616 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H32F2N4O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 46 / 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: 2.26 Å3/Da / Density % sol: 51.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 18 % PEG8000, 2 % 2-Propanol, 0.1 M Sodium acetate, 0.1 M HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.972422 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.972422 Å / Relative weight: 1
ReflectionResolution: 2.2→73.43 Å / Num. obs: 13112 / % possible obs: 99.2 % / Redundancy: 3.3 % / CC1/2: 0.995 / Rmerge(I) obs: 0.124 / Rpim(I) all: 0.081 / Net I/σ(I): 6.6
Reflection shellResolution: 2.2→2.27 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.694 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 1111 / CC1/2: 0.709 / Rpim(I) all: 0.466 / % possible all: 99

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROCdata processing
autoPROCdata scaling
MOLREPphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1M2Z

1m2z


Resolution: 2.2→42.26 Å / Cor.coef. Fo:Fc: 0.914 / Cor.coef. Fo:Fc free: 0.901 / SU R Cruickshank DPI: 0.371 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.352 / SU Rfree Blow DPI: 0.25 / SU Rfree Cruickshank DPI: 0.256
RfactorNum. reflection% reflectionSelection details
Rfree0.2808 658 -RANDOM
Rwork0.2256 ---
obs0.2286 13075 99 %-
Displacement parametersBiso mean: 50.78 Å2
Baniso -1Baniso -2Baniso -3
1--11.7207 Å20 Å2-19.1358 Å2
2--11.1885 Å20 Å2
3---0.5322 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: LAST / Resolution: 2.2→42.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2168 0 44 46 2258
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082265HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.973069HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d797SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes377HARMONIC5
X-RAY DIFFRACTIONt_it2265HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion288SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2016SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.79
X-RAY DIFFRACTIONt_other_torsion17.91
LS refinement shellResolution: 2.2→2.22 Å
RfactorNum. reflection% reflection
Rfree0.341 22 -
Rwork0.3055 --
obs0.3076 409 95.49 %
Refinement TLS params.

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)
11.61291.26650.26434.42251.06411.7011-0.010.11570.14350.11570.06780.05630.14350.0563-0.0578-0.19210.02170.1765-0.30890.02840.193735.0791-0.369947.2282
21.8358-3.1333-5.39714.59048.738415.25-0.3588-0.228-0.3205-0.228-0.0872-0.0844-0.3205-0.08440.4460.1533-0.13020.2625-0.1801-0.03730.014823.66447.392264.2446
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A529 - 776
2X-RAY DIFFRACTION2{ B|* }B134 - 152

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