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- PDB-8f5y: Crystal structure of pregnane X receptor ligand binding domain co... -

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Basic information

Entry
Database: PDB / ID: 8f5y
TitleCrystal structure of pregnane X receptor ligand binding domain complexed with JQ1
Components
  • Nuclear receptor coactivator 1
  • Nuclear receptor subfamily 1 group I member 2
KeywordsTRANSCRIPTION / nuclear receptor / transcription factor / metabolism / antibiotic
Function / homology
Function and homology information


labyrinthine layer morphogenesis / xenobiotic transport / regulation of thyroid hormone mediated signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / intermediate filament cytoskeleton / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / steroid metabolic process ...labyrinthine layer morphogenesis / xenobiotic transport / regulation of thyroid hormone mediated signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / intermediate filament cytoskeleton / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / steroid metabolic process / estrous cycle / cellular response to Thyroglobulin triiodothyronine / Synthesis of bile acids and bile salts / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / xenobiotic catabolic process / nuclear retinoid X receptor binding / response to retinoic acid / histone acetyltransferase activity / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / histone acetyltransferase / cellular response to hormone stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / lactation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / xenobiotic metabolic process / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / response to progesterone / nuclear estrogen receptor binding / nuclear receptor binding / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Heme signaling / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / cerebral cortex development / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / male gonad development / nuclear receptor activity / Circadian Clock / sequence-specific double-stranded DNA binding / response to estradiol / HATs acetylate histones / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / transcription regulator complex / cell differentiation / transcription coactivator activity / nuclear body / protein dimerization activity / DNA-binding transcription factor activity, RNA polymerase II-specific / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of DNA-templated transcription / chromatin binding / chromatin / positive regulation of gene expression / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / signal transduction / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm / nucleus / plasma membrane / cytosol
Similarity search - Function
Nuclear receptor coactivator 1 / 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 ...Nuclear receptor coactivator 1 / 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 / 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. / Nuclear receptor coactivator, interlocking / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily / 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
Similarity search - Domain/homology
Chem-JQ1 / Nuclear receptor subfamily 1 group I member 2 / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsHuber, A.D. / Poudel, S. / Seetharaman, J. / Miller, D.J. / Chen, T.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM118041 United States
CitationJournal: Nucleic Acids Res. / Year: 2024
Title: A bromodomain-independent mechanism of gene regulation by the BET inhibitor JQ1: direct activation of nuclear receptor PXR.
Authors: Huber, A.D. / Poudel, S. / Wu, J. / Miller, D.J. / Lin, W. / Yang, L. / Bwayi, M.N. / Rimmer, M.A. / Gee, R.R.F. / Seetharaman, J. / Chai, S.C. / Chen, T.
History
DepositionNov 15, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 21, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nuclear receptor subfamily 1 group I member 2
B: Nuclear receptor subfamily 1 group I member 2
C: Nuclear receptor coactivator 1
D: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,9466
Polymers78,0304
Non-polymers9162
Water1,72996
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3970 Å2
ΔGint-31 kcal/mol
Surface area25180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.547, 82.562, 103.669
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 142 through 144 or (resid 145...
d_2ens_1(chain "B" and (resid 142 through 169 or resid 171...
d_1ens_2(chain "C" and resid 685 through 695)
d_2ens_2(chain "D" and (resid 685 through 687 or (resid 688...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1GLYGLYPHEPHEAA142 - 16924 - 51
d_12ens_1ASNASNGLYGLYAA171 - 17653 - 58
d_13ens_1LYSLYSVALVALAA210 - 21192 - 93
d_14ens_1LEULEUGLUGLUAA213 - 21895 - 100
d_15ens_1GLYGLYTYRTYRAA220 - 225102 - 107
d_16ens_1PROPROPROPROAA227 - 228109 - 110
d_17ens_1SERSERILEILEAA238 - 269120 - 151
d_18ens_1ASPASPLEULEUAA271 - 283153 - 165
d_19ens_1GLNGLNTYRTYRAA285 - 306167 - 188
d_110ens_1LEULEULEULEUAA308190
d_111ens_1GLUGLUTYRTYRAA321 - 328203 - 210
d_112ens_1LEULEUGLNGLNAA330 - 358212 - 240
d_113ens_1ARGARGGLNGLNAA360 - 366242 - 248
d_114ens_1GLNGLNHISHISAA368 - 386250 - 268
d_115ens_1PHEPHEALAALAAA388 - 405270 - 287
d_116ens_1THRTHRTHRTHRAA408290
d_117ens_1LEULEULEULEUAA411 - 412293 - 294
d_118ens_1ILEILEILEILEAA414 - 431296 - 313
d_119ens_1JQ1JQ1JQ1JQ1AE501
d_21ens_1GLYGLYPHEPHEBB142 - 16924 - 51
d_22ens_1ASNASNGLYGLYBB171 - 17653 - 58
d_23ens_1LYSLYSVALVALBB210 - 21192 - 93
d_24ens_1LEULEUGLUGLUBB213 - 21895 - 100
d_25ens_1GLYGLYTYRTYRBB220 - 225102 - 107
d_26ens_1PROPROILEILEBB227 - 269109 - 151
d_27ens_1ASPASPLEULEUBB271 - 283153 - 165
d_28ens_1GLNGLNTYRTYRBB285 - 306167 - 188
d_29ens_1LEULEUTYRTYRBB308 - 328190 - 210
d_210ens_1LEULEUGLNGLNBB330 - 358212 - 240
d_211ens_1ARGARGGLNGLNBB360 - 366242 - 248
d_212ens_1GLNGLNHISHISBB368 - 386250 - 268
d_213ens_1PHEPHEALAALABB388 - 405270 - 287
d_214ens_1THRTHRTHRTHRBB408290
d_215ens_1LEULEULEULEUBB411 - 412293 - 294
d_216ens_1ILEILEILEILEBB414 - 431296 - 313
d_217ens_1JQ1JQ1JQ1JQ1BF501
d_11ens_2GLUGLUGLNGLNCC685 - 69510 - 20
d_21ens_2GLUGLUGLNGLNDD685 - 69510 - 20

NCS ensembles :
ID
ens_1
ens_2

NCS oper: (Code: givenMatrix: (-0.976090086405, 0.128059925713, 0.175638260775), (0.190698317067, 0.116716515788, 0.974685286033), (0.104318239486, 0.984874565805, -0.138346646297)Vector: 54. ...NCS oper: (Code: given
Matrix: (-0.976090086405, 0.128059925713, 0.175638260775), (0.190698317067, 0.116716515788, 0.974685286033), (0.104318239486, 0.984874565805, -0.138346646297)
Vector: 54.3294286431, 5.71443112547, -15.769759111)

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Components

#1: Protein Nuclear receptor subfamily 1 group I member 2 / Orphan nuclear receptor PAR1 / Orphan nuclear receptor PXR / Pregnane X receptor / Steroid and ...Orphan nuclear receptor PAR1 / Orphan nuclear receptor PXR / Pregnane X receptor / Steroid and xenobiotic receptor / SXR


Mass: 36208.742 Da / Num. of mol.: 2 / Fragment: UNP residues 153-457
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1I2, PXR / Production host: Escherichia coli (E. coli) / References: UniProt: O75469
#2: Protein/peptide Nuclear receptor coactivator 1 / / NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal ...NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal carcinoma antigen NY-REN-52 / Steroid receptor coactivator 1 / SRC-1


Mass: 2806.163 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-JQ1 / (6S)-6-(2-tert-butoxy-2-oxoethyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6,7-dihydrothieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-10-ium / JQ1


Mass: 457.996 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H26ClN4O2S / Feature type: SUBJECT OF INVESTIGATION / Comment: inhibitor*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 96 / 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: 2.11 Å3/Da / Density % sol: 41.7 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 50 mM imidazole pH 7.0, 8% isopropanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.9201 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: May 27, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.15→43.9 Å / Num. obs: 36061 / % possible obs: 99.8 % / Redundancy: 6.7 % / Biso Wilson estimate: 40.34 Å2 / CC1/2: 0.999 / Rsym value: 0.084 / Net I/σ(I): 12.9
Reflection shellResolution: 2.15→2.21 Å / Redundancy: 6.3 % / Mean I/σ(I) obs: 2.3 / Num. unique obs: 2900 / CC1/2: 0.829 / Rsym value: 0.797 / % possible all: 98.7

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1NRL

1nrl


Resolution: 2.15→32.61 Å / SU ML: 0.2655 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 23.3715
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2155 1726 4.8 %
Rwork0.2067 34259 -
obs0.2071 35985 99.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 49.28 Å2
Refinement stepCycle: LAST / Resolution: 2.15→32.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4318 0 62 96 4476
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00714524
X-RAY DIFFRACTIONf_angle_d0.93346124
X-RAY DIFFRACTIONf_chiral_restr0.0587672
X-RAY DIFFRACTIONf_plane_restr0.0077776
X-RAY DIFFRACTIONf_dihedral_angle_d15.57641644
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS1.06864664366
ens_2d_2CCX-RAY DIFFRACTIONTorsion NCS1.18922093853
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.210.32961410.27922799X-RAY DIFFRACTION98.76
2.21-2.280.29191400.25792798X-RAY DIFFRACTION99.9
2.28-2.360.25961400.23552817X-RAY DIFFRACTION99.93
2.36-2.460.24771480.23412814X-RAY DIFFRACTION99.9
2.46-2.570.27981440.23492821X-RAY DIFFRACTION100
2.57-2.710.28291510.24322831X-RAY DIFFRACTION100
2.71-2.880.25071700.22512826X-RAY DIFFRACTION99.93
2.88-3.10.22951300.22852852X-RAY DIFFRACTION100
3.1-3.410.23121220.22592877X-RAY DIFFRACTION99.87
3.41-3.90.19161260.19382900X-RAY DIFFRACTION99.8
3.9-4.910.16771580.16712906X-RAY DIFFRACTION99.84
4.91-32.610.19161560.19213018X-RAY DIFFRACTION99.69

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