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- PDB-9o45: Crystal structure of the L411W mutant of pregnane X receptor liga... -

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Basic information

Entry
Database: PDB / ID: 9o45
TitleCrystal structure of the L411W mutant of pregnane X receptor ligand binding domain in complex with SJPYT-328
ComponentsPregnane X receptor ligand binding domain tethered to steroid receptor coactivator-1 peptide
KeywordsTRANSCRIPTION / Pregnane X receptor / PXR / NR1I2 / transcription factor / nuclear receptor / drug metabolism
Function / homology
Function and homology information


cellular response to molecule of bacterial origin / intestinal epithelial structure maintenance / intermediate filament cytoskeleton / labyrinthine layer morphogenesis / positive regulation of transcription from RNA polymerase II promoter by galactose / regulation of thyroid hormone receptor signaling pathway / positive regulation of female receptivity / xenobiotic transport / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / male mating behavior ...cellular response to molecule of bacterial origin / intestinal epithelial structure maintenance / intermediate filament cytoskeleton / labyrinthine layer morphogenesis / positive regulation of transcription from RNA polymerase II promoter by galactose / regulation of thyroid hormone receptor signaling pathway / positive regulation of female receptivity / xenobiotic transport / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / male mating behavior / hypothalamus development / steroid metabolic process / cellular response to Thyroglobulin triiodothyronine / Synthesis of bile acids and bile salts / progesterone receptor signaling pathway / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / response to retinoic acid / xenobiotic catabolic process / estrous cycle / nuclear retinoid X receptor binding / histone acetyltransferase activity / cellular response to hormone stimulus / Recycling of bile acids and salts / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / histone acetyltransferase / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / intracellular receptor signaling pathway / estrogen receptor signaling pathway / lactation / : / positive regulation of adipose tissue development / Regulation of lipid metabolism by PPARalpha / peroxisome proliferator activated receptor signaling pathway / positive regulation of neuron differentiation / regulation of cellular response to insulin stimulus / xenobiotic metabolic process / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / response to progesterone / cerebellum development / nuclear estrogen receptor binding / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / hippocampus development / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / cerebral cortex development / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / RNA polymerase II transcription regulator complex / male gonad development / nuclear receptor activity / sequence-specific double-stranded DNA binding / : / response to estradiol / HATs acetylate histones / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / DNA-binding transcription activator activity, RNA polymerase II-specific / transcription regulator complex / Estrogen-dependent gene expression / DNA-binding transcription factor activity, RNA polymerase II-specific / cell differentiation / transcription coactivator activity / protein dimerization activity / 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 / positive regulation of gene expression / regulation of DNA-templated transcription / chromatin / positive regulation of DNA-templated transcription / protein-containing complex binding / 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 / : ...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 / Nuclear receptor coactivators bHLH domain / 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 / PAS 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
Similarity search - Domain/homology
: / 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: 2.56 Å
AuthorsHuber, A.D. / Garcia-Maldonado, E. / 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: Structure / Year: 2025
Title: Subtle changes in ligand-receptor interactions dramatically alter transcriptional outcomes of pregnane X receptor modulators.
Authors: Huber, A.D. / Garcia-Maldonado, E. / Lin, W. / Poudel, S. / Wu, J. / Miller, D.J. / Chen, T.
History
DepositionApr 8, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 5, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Pregnane X receptor ligand binding domain tethered to steroid receptor coactivator-1 peptide
B: Pregnane X receptor ligand binding domain tethered to steroid receptor coactivator-1 peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,8484
Polymers80,8312
Non-polymers1,0172
Water50428
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1690 Å2
ΔGint-13 kcal/mol
Surface area26400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.002, 88.525, 105.076
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

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Components

#1: Protein Pregnane X receptor ligand binding domain tethered to steroid receptor coactivator-1 peptide / 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: 40415.297 Da / Num. of mol.: 2 / Mutation: L411W
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1I2, PXR, NCOA1, BHLHE74, SRC1 / Production host: Escherichia coli (E. coli)
References: UniProt: O75469, UniProt: Q15788, histone acetyltransferase
#2: Chemical ChemComp-WU2 / (1P)-N-(5-tert-butyl-2-{[(3S)-hexan-3-yl]oxy}phenyl)-1-(2,4-dimethoxy-5-methylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide


Mass: 508.652 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H40N4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.47 Å3/Da / Density % sol: 50.3 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 50 mM Bis-Tris (pH 6-7), 9-16% (v/v) 2-methyl-2,4-pentanediol
PH range: 6-7

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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: Jun 3, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.56→45.18 Å / Num. obs: 26319 / % possible obs: 99.9 % / Redundancy: 7.4 % / Biso Wilson estimate: 61.23 Å2 / CC1/2: 0.997 / Rsym value: 0.097 / Net I/σ(I): 11
Reflection shellResolution: 2.56→2.67 Å / Redundancy: 7.7 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 3134 / CC1/2: 0.769 / Rsym value: 0.863 / % possible all: 99.1

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.56→45.18 Å / SU ML: 0.3235 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.4353
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2408 1488 5.67 %
Rwork0.1999 24769 -
obs0.2023 26257 99.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 71.42 Å2
Refinement stepCycle: LAST / Resolution: 2.56→45.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4581 0 74 28 4683
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00354775
X-RAY DIFFRACTIONf_angle_d0.62026464
X-RAY DIFFRACTIONf_chiral_restr0.0378709
X-RAY DIFFRACTIONf_plane_restr0.0083820
X-RAY DIFFRACTIONf_dihedral_angle_d14.02551716
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.56-2.640.35941120.27032212X-RAY DIFFRACTION98.85
2.64-2.730.34681320.27832233X-RAY DIFFRACTION99.96
2.73-2.840.33471380.26082213X-RAY DIFFRACTION99.96
2.84-2.970.30111320.22842199X-RAY DIFFRACTION99.96
2.97-3.130.31191110.23282260X-RAY DIFFRACTION100
3.13-3.320.29741320.22672243X-RAY DIFFRACTION100
3.32-3.580.26431430.20332233X-RAY DIFFRACTION99.96
3.58-3.940.22641460.19262240X-RAY DIFFRACTION99.96
3.94-4.510.21631420.17462266X-RAY DIFFRACTION99.88
4.51-5.680.21031650.17692264X-RAY DIFFRACTION100
5.68-45.180.20231350.18822406X-RAY DIFFRACTION99.45

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