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- PDB-8svq: Crystal structure of pregnane X receptor ligand binding domain in... -

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Basic information

Entry
Database: PDB / ID: 8svq
TitleCrystal structure of pregnane X receptor ligand binding domain in complex with SJPYT-312
ComponentsPregnane X receptor ligand binding domain fused to SRC-1 coactivator peptide
KeywordsTRANSCRIPTION / Pregnane X receptor (PXR) / promiscuous ligand-activated protein / nuclear receptor subfamily 1 / transcriptional regulator / and drug metabolism.
Function / homology
Function and homology information


xenobiotic transport / labyrinthine layer morphogenesis / 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 ...xenobiotic transport / labyrinthine layer morphogenesis / 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 / hippocampus development / nuclear receptor binding / 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 / 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 / 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 / regulation of DNA-templated transcription / positive regulation of gene expression / 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 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 / 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
: / Nuclear receptor subfamily 1 group I member 2 / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.75 Å
AuthorsGarcia-Maldonado, E. / Huber, A.D. / Nithianantham, S. / 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: Nat Commun / Year: 2024
Title: Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR.
Authors: Garcia-Maldonado, E. / Huber, A.D. / Chai, S.C. / Nithianantham, S. / Li, Y. / Wu, J. / Poudel, S. / Miller, D.J. / Seetharaman, J. / Chen, T.
History
DepositionMay 17, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 15, 2024Provider: repository / Type: Initial release
Revision 1.1May 29, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)80,8595
Polymers79,7912
Non-polymers1,0673
Water18010
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Dimer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2060 Å2
ΔGint-12 kcal/mol
Surface area26230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.329, 87.904, 104.534
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Pregnane X receptor ligand binding domain fused to SRC-1 coactivator peptide


Mass: 39895.633 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1I2, PXR, NCOA1, BHLHE74, SRC1 / Plasmid: pET-3A / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: O75469, UniProt: Q15788, histone acetyltransferase
#2: Chemical ChemComp-WSX / (1P)-N-(5-tert-butyl-2-{[(3S)-hexan-3-yl]oxy}phenyl)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide


Mass: 494.626 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H38N4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 10 / Source method: obtained synthetically / 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: 2.43 Å3/Da / Density % sol: 49.34 % / Description: Rectangular shaped crystal
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 50 mM Bis-Tris pH 6.0-7.0, 9-16% (v/v) 2-Methyl-2,4-pentanediol
PH range: 6.0-7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 22, 2022
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.75→84.33 Å / Num. obs: 20837 / % possible obs: 100 % / Redundancy: 10.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.113 / Rpim(I) all: 0.037 / Rrim(I) all: 0.119 / Χ2: 1.01 / Net I/σ(I): 12.4 / Num. measured all: 217642
Reflection shellResolution: 2.75→2.88 Å / % possible obs: 100 % / Redundancy: 11 % / Rmerge(I) obs: 1.407 / Num. measured all: 29732 / Num. unique obs: 2709 / CC1/2: 0.685 / Rpim(I) all: 0.443 / Rrim(I) all: 1.476 / Χ2: 1.04 / Net I/σ(I) obs: 1.8

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487)refinement
Aimlessdata scaling
XDSdata reduction
PHENIX(1.20.1_4487)phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.75→67.28 Å / SU ML: 0.42 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 28.26 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2618 1000 4.81 %Random selection
Rwork0.2301 ---
obs0.2334 20787 99.96 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.75→67.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4467 0 76 10 4553
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024643
X-RAY DIFFRACTIONf_angle_d0.4736274
X-RAY DIFFRACTIONf_dihedral_angle_d13.041690
X-RAY DIFFRACTIONf_chiral_restr0.032701
X-RAY DIFFRACTIONf_plane_restr0.005790
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.75-2.90.40091620.35472733X-RAY DIFFRACTION100
2.9-3.080.30231140.27852811X-RAY DIFFRACTION100
3.08-3.310.28321260.27342799X-RAY DIFFRACTION100
3.31-3.650.31051510.25952805X-RAY DIFFRACTION100
3.65-4.180.27481460.22162822X-RAY DIFFRACTION100
4.18-5.260.24631650.21012829X-RAY DIFFRACTION100
5.26-67.280.22251360.21062988X-RAY DIFFRACTION100

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