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- PDB-4p6w: Crystal Structure of mometasone furoate-bound glucocorticoid rece... -

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Basic information

Entry
Database: PDB / ID: 4p6w
TitleCrystal Structure of mometasone furoate-bound glucocorticoid receptor ligand binding domain
Components
  • Glucocorticoid receptor
  • Nuclear receptor coactivator 2
KeywordsHORMONE RECEPTOR/HORMONE ACTIVATOR / mometasone furoate / glucocorticoid receptor / potency / HORMONE-HORMONE RECEPTOR complex / HORMONE RECEPTOR-HORMONE ACTIVATOR 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 / estrogen response element binding / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / 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 / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / 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 / SUMOylation of intracellular receptors / Heme signaling / 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 / Regulation of RUNX2 expression and activity / positive regulation of neuron apoptotic process / 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
MOMETASONE FUROATE / Glucocorticoid receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.951 Å
AuthorsHe, Y. / Zhou, X.E. / Tolbert, W.D. / Powell, K. / Melcher, K. / Xu, H.E.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK066202 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK071662 United States
AAF2010 senior award United States
CitationJournal: Cell Res. / Year: 2014
Title: Structures and mechanism for the design of highly potent glucocorticoids.
Authors: He, Y. / Yi, W. / Suino-Powell, K. / Zhou, X.E. / Tolbert, W.D. / Tang, X. / Yang, J. / Yang, H. / Shi, J. / Hou, L. / Jiang, H. / Melcher, K. / Xu, H.E.
History
DepositionMar 25, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 16, 2014Provider: repository / Type: Initial release
Revision 1.1May 7, 2014Group: Database references
Revision 1.2Jul 16, 2014Group: Database references
Revision 1.3Sep 27, 2017Group: Author supporting evidence / Derived calculations ...Author supporting evidence / Derived calculations / Other / Refinement description / Source and taxonomy
Category: entity_src_gen / pdbx_audit_support ...entity_src_gen / pdbx_audit_support / pdbx_database_status / pdbx_entity_src_syn / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list / software
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization ..._entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization / _pdbx_database_status.pdb_format_compatible / _pdbx_entity_src_syn.pdbx_alt_source_flag / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Dec 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glucocorticoid receptor
B: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,2123
Polymers30,6912
Non-polymers5211
Water2,342130
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2170 Å2
ΔGint-26 kcal/mol
Surface area13100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)130.218, 130.218, 130.218
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number195
Space group name H-MP23

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Components

#1: Protein Glucocorticoid receptor / / GR / Nuclear receptor subfamily 3 group C member 1


Mass: 29284.033 Da / Num. of mol.: 1 / Fragment: Ligand binding domain (UNP residues 526-777) / Mutation: F602A, C622Y, T668V, S674T, V675I, K699A, K703A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR3C1, GRL / Production host: Escherichia coli (E. coli) / Strain (production host): K-12 / References: UniProt: P04150
#2: Protein/peptide Nuclear receptor coactivator 2 / / NCoA-2 / Class E basic helix-loop-helix protein 75 / bHLHe75 / Transcriptional intermediary factor 2 / hTIF2


Mass: 1406.628 Da / Num. of mol.: 1 / Fragment: SRC2-3 peptide (UNP residues 741-752) / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-MOF / MOMETASONE FUROATE / Mometasone


Mass: 521.429 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H30Cl2O6 / Comment: medication*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 130 / 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: 6 Å3/Da / Density % sol: 79.48 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1 M imidazole, pH6.5, and 1 M sodium acetate trihydrate. 30% sucrose

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.987 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 6, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.95→30 Å / Num. obs: 53521 / % possible obs: 99.4 % / Redundancy: 10.2 % / Rmerge(I) obs: 0.128 / Net I/σ(I): 23.5

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Processing

Software
NameVersionClassificationNB
PDB_EXTRACT3.14data extraction
PHENIX1.8.4_1496refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.951→29.874 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2248 4364 8.18 %
Rwork0.2104 --
obs0.2116 53320 99.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 96.84 Å2 / Biso mean: 37.8057 Å2 / Biso min: 19.41 Å2
Refinement stepCycle: final / Resolution: 1.951→29.874 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2150 0 35 130 2315
Biso mean--37.65 39.42 -
Num. residues----264

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