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

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Basic information

Entry
Database: PDB / ID: 8svs
TitleCrystal structure of pregnane X receptor ligand binding domain in complex with SJPYT-328
ComponentsNuclear receptor subfamily 1 group I member 2, Nuclear receptor coactivator 1 fusion protein,Nuclear receptor coactivator 1
KeywordsTRANSCRIPTION / Pregnane X receptor (PXR) / promiscuous ligand-activated protein / nuclear receptor subfamily 1 / transcriptional regulator / 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: 2.68 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 1.1Jun 5, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)80,8094
Polymers79,7912
Non-polymers1,0172
Water724
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Dimer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1410 Å2
ΔGint-11 kcal/mol
Surface area25820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.469, 88.264, 107.256
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 Nuclear receptor subfamily 1 group I member 2, Nuclear receptor coactivator 1 fusion protein,Nuclear receptor coactivator 1 / 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
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-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.: 4 / 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: 2.51 Å3/Da / Density % sol: 50.91 % / 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: Oct 6, 2022
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.68→88.26 Å / Num. obs: 22874 / % possible obs: 98.7 % / Redundancy: 12.1 % / CC1/2: 0.998 / Rmerge(I) obs: 0.093 / Rpim(I) all: 0.027 / Rrim(I) all: 0.097 / Χ2: 0.96 / Net I/σ(I): 14.3 / Num. measured all: 277353
Reflection shellResolution: 2.68→2.81 Å / % possible obs: 91.7 % / Redundancy: 7.6 % / Rmerge(I) obs: 0.827 / Num. measured all: 20887 / Num. unique obs: 2764 / CC1/2: 0.642 / Rpim(I) all: 0.315 / Rrim(I) all: 0.888 / Χ2: 0.86 / Net I/σ(I) obs: 2

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.68→61.03 Å / SU ML: 0.46 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 32.62 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2503 1174 5.15 %Random selection
Rwork0.2237 ---
obs0.2251 22800 98.55 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.68→61.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4423 0 74 4 4501
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024602
X-RAY DIFFRACTIONf_angle_d0.4136219
X-RAY DIFFRACTIONf_dihedral_angle_d14.1191674
X-RAY DIFFRACTIONf_chiral_restr0.033689
X-RAY DIFFRACTIONf_plane_restr0.004785
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.68-2.80.43461330.41342443X-RAY DIFFRACTION91
2.8-2.950.40861420.31432645X-RAY DIFFRACTION98
2.95-3.130.28821450.26732704X-RAY DIFFRACTION100
3.13-3.380.31481370.27842727X-RAY DIFFRACTION100
3.38-3.720.25931450.22872707X-RAY DIFFRACTION100
3.72-4.250.23431520.21232749X-RAY DIFFRACTION100
4.25-5.360.23681380.19052780X-RAY DIFFRACTION100
5.36-61.030.21661820.20442871X-RAY DIFFRACTION100

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