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- PDB-6nx1: STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUN... -

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Basic information

Entry
Database: PDB / ID: 6nx1
TitleSTRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUND TETHERED WITH SRC CO-ACTIVATOR PEPTIDE AND COMPOUND-3 AKA 1,1,1,3,3,3-HEXAFLUORO-2-{4-[1-(4- LUOROBENZENESULFONYL)CYCLOPENTYL]PHENYL}PROPAN-2-OL
ComponentsNuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1 fusion
KeywordsTRANSFERASE / MULTIPLE BINDING MODES / XENOBIOTIC / PROMISCUOUS / NUCLEAR HORMONE RECEPTOR / PXR / RORgT
Function / homology
Function and homology information


labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / intermediate filament cytoskeleton / xenobiotic transport / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / steroid metabolic process ...labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / intermediate filament cytoskeleton / xenobiotic transport / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / steroid metabolic process / cellular response to Thyroglobulin triiodothyronine / Synthesis of bile acids and bile salts / estrous cycle / 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 / progesterone receptor signaling pathway / nuclear retinoid X receptor binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / response to retinoic acid / histone acetyltransferase activity / Recycling of bile acids and salts / histone acetyltransferase / cellular response to hormone stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / estrogen receptor signaling pathway / positive regulation of adipose tissue development / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / lactation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / xenobiotic metabolic process / regulation of cellular response to insulin stimulus / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian gene expression / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / response to progesterone / nuclear receptor binding / nuclear estrogen receptor binding / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / SUMOylation of intracellular receptors / Heme signaling / 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 / nuclear receptor activity / male gonad development / sequence-specific double-stranded DNA binding / Circadian Clock / response to estradiol / HATs acetylate histones / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / transcription regulator complex / transcription coactivator activity / cell differentiation / protein dimerization activity / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear body / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of DNA-templated transcription / chromatin binding / regulation of DNA-templated transcription / positive regulation of gene expression / chromatin / 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 / : / Nuclear receptor coactivator, interlocking / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / Retinoid X Receptor / Retinoid X Receptor / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-L7D / Nuclear receptor subfamily 1 group I member 2 / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.27 Å
AuthorsKhan, J.A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as Selective, Orally Active ROR gamma t Inverse Agonists.
Authors: Duan, J.J. / Lu, Z. / Jiang, B. / Stachura, S. / Weigelt, C.A. / Sack, J.S. / Khan, J. / Ruzanov, M. / Galella, M.A. / Wu, D.R. / Yarde, M. / Shen, D.R. / Shuster, D.J. / Borowski, V. / Xie, ...Authors: Duan, J.J. / Lu, Z. / Jiang, B. / Stachura, S. / Weigelt, C.A. / Sack, J.S. / Khan, J. / Ruzanov, M. / Galella, M.A. / Wu, D.R. / Yarde, M. / Shen, D.R. / Shuster, D.J. / Borowski, V. / Xie, J.H. / Zhang, L. / Vanteru, S. / Gupta, A.K. / Mathur, A. / Zhao, Q. / Foster, W. / Salter-Cid, L.M. / Carter, P.H. / Dhar, T.G.M.
History
DepositionFeb 7, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)80,7324
Polymers79,7912
Non-polymers9412
Water1,09961
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area860 Å2
ΔGint-4 kcal/mol
Surface area27530 Å2
2
A: Nuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1 fusion
hetero molecules

B: Nuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1 fusion
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,7324
Polymers79,7912
Non-polymers9412
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_544-x,y-1/2,-z-1/21
Buried area1820 Å2
ΔGint-15 kcal/mol
Surface area26580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.195, 89.612, 106.158
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Nuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1 fusion / 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 / 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: 39895.633 Da / Num. of mol.: 2 / Fragment: LIGAND BINDING DOMAIN
Source method: isolated from a genetically manipulated source
Details: PXR-LBD(130-434)WITH TETHERED SRC DOMAIN(678-710) / Source: (gene. exp.) Homo sapiens (human) / Gene: NR1I2, PXR, NCOA1, BHLHE74, SRC1 / Plasmid: pET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: O75469, UniProt: Q15788, histone acetyltransferase
#2: Chemical ChemComp-L7D / 1,1,1,3,3,3-hexafluoro-2-(4-{1-[(4-fluorophenyl)sulfonyl]cyclopentyl}phenyl)propan-2-ol


Mass: 470.401 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H17F7O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 61 / 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: 2.51 Å3/Da / Density % sol: 50.99 %
Crystal growTemperature: 296 K / Method: vapor diffusion, hanging drop
Details: 0.1M Hepes pH 7.5, 150mM NaCl, 10-15%(V/V)PEG10K, Crystals were cryoprotected by supplementing the mother liquor with 15% (v/v) ethylene glycol and harvested by flash-cooling in liquid nitrogen
PH range: 7.5- 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 1 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Sep 15, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.27→50 Å / Num. obs: 37903 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 6.1 % / Biso Wilson estimate: 58.38 Å2 / Rmerge(I) obs: 0.054 / Rsym value: 0.02 / Net I/σ(I): 28.9
Reflection shellResolution: 2.27→2.35 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0.437 / Mean I/σ(I) obs: 3.8 / % possible all: 99.8

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementResolution: 2.27→42.1 Å / Cor.coef. Fo:Fc: 0.9442 / Cor.coef. Fo:Fc free: 0.924 / SU R Cruickshank DPI: 0.236 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.232 / SU Rfree Blow DPI: 0.188 / SU Rfree Cruickshank DPI: 0.191
RfactorNum. reflection% reflectionSelection details
Rfree0.2397 1881 4.99 %RANDOM
Rwork0.2107 ---
obs0.2122 37732 99.85 %-
Displacement parametersBiso max: 166.73 Å2 / Biso mean: 62.86 Å2 / Biso min: 20 Å2
Baniso -1Baniso -2Baniso -3
1--6.6612 Å20 Å20 Å2
2--0.2395 Å20 Å2
3---6.4217 Å2
Refine analyzeLuzzati coordinate error obs: 0.321 Å
Refinement stepCycle: final / Resolution: 2.27→42.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4526 0 87 61 4674
Biso mean--75.51 55.83 -
Num. residues----582
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1617SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes95HARMONIC2
X-RAY DIFFRACTIONt_gen_planes722HARMONIC5
X-RAY DIFFRACTIONt_it4734HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion620SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5489SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4734HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6438HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion2.58
X-RAY DIFFRACTIONt_other_torsion18.64
LS refinement shellResolution: 2.27→2.33 Å / Rfactor Rfree error: 0 / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.2437 143 5 %
Rwork0.2384 2718 -
all0.2386 2861 -
obs--99.85 %

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