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- PDB-8svu: Crystal structure of the L428V mutant of pregnane X receptor liga... -

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Basic information

Entry
Database: PDB / ID: 8svu
TitleCrystal structure of the L428V mutant of pregnane X receptor ligand binding domain in apo form
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


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 / MOLECULAR REPLACEMENT / Resolution: 2.89 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

Downloads & links

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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)79,8553
Polymers79,7632
Non-polymers921
Water905
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Dimer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1700 Å2
ΔGint-11 kcal/mol
Surface area26850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.275, 89.778, 106.121
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: 39881.605 Da / Num. of mol.: 2 / Mutation: L428V
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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.55 Å3/Da / Density % sol: 51.7 % / 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: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: May 3, 2023
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.89→29.68 Å / Num. obs: 18765 / % possible obs: 99.6 % / Redundancy: 6.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.096 / Rpim(I) all: 0.04 / Rrim(I) all: 0.104 / Χ2: 1 / Net I/σ(I): 13.1 / Num. measured all: 124670
Reflection shellResolution: 2.89→3.07 Å / % possible obs: 98.1 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.893 / Num. measured all: 19335 / Num. unique obs: 2923 / CC1/2: 0.719 / Rpim(I) all: 0.372 / Rrim(I) all: 0.969 / Χ2: 1.01 / Net I/σ(I) obs: 2.2

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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: 2.89→28.8 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 24.41 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2441 886 4.73 %Random selection
Rwork0.2042 ---
obs0.2061 18719 99.66 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.89→28.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4398 0 6 5 4409
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044502
X-RAY DIFFRACTIONf_angle_d0.5516084
X-RAY DIFFRACTIONf_dihedral_angle_d12.8661634
X-RAY DIFFRACTIONf_chiral_restr0.039688
X-RAY DIFFRACTIONf_plane_restr0.004779
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.89-3.070.29221520.25692854X-RAY DIFFRACTION98
3.07-3.310.29391550.25022937X-RAY DIFFRACTION100
3.31-3.640.27261460.21492939X-RAY DIFFRACTION100
3.64-4.170.23561160.19572994X-RAY DIFFRACTION100
4.17-5.240.22281370.18523009X-RAY DIFFRACTION100
5.25-28.80.23191800.19883100X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.67770.0285-0.67740.68240.15890.5693-0.19710.17520.79880.02630.00180.2217-0.5255-0.0443-0.00170.51720.008-0.09890.4369-0.01470.527228.814126.439835.6672
2-0.0132-0.0042-0.025-0.02280.00640.0105-0.57-0.2066-0.29572.09680.4382-0.0662-0.30710.4183-01.64280.1814-0.11820.8304-0.27141.483835.1691.164413.9229
30.55990.26830.21490.4603-0.00730.12250.4169-0.0768-0.1278-0.0623-0.5408-0.19870.2079-0.5472-0.02420.80580.0187-0.10591.0811-0.31460.856617.30678.610920.434
42.0747-0.50040.49591.46530.02562.7557-0.0462-0.0330.08480.0767-0.0482-0.14630.1510.13840.00010.46630.009-0.01560.4155-0.00040.506136.240418.76435.4364
5-0.31910.630.35850.1773-0.23820.54230.0190.2436-0.1385-0.19630.0226-0.19080.28050.604100.68570.0467-0.01830.734-0.00220.601239.585318.069622.6414
60.1902-0.0117-0.01710.0985-0.12620.17390.29860.4837-0.4238-0.312-0.373-0.2491-0.1363-0.354-00.59430.01290.01070.7376-0.09360.6709-12.0429-10.4084-8.561
70.0876-0.18220.39350.6456-0.03470.3433-0.572-0.22820.4305-0.04290.23990.7318-0.091.0007-0.00090.7334-0.08770.07330.8684-0.0580.8923-2.16599.449811.6551
80.28290.0280.05630.621-0.39620.2962-0.0926-0.8894-0.4713-0.03560.5280.24660.1024-0.09920.07210.6788-0.116-0.05761.0166-0.4120.84934.05339.816320.0712
92.48910.5787-0.80932.24230.6841.31080.1017-0.17970.22830.1962-0.050.1921-0.0955-0.074800.4850.0074-0.02570.4631-0.01470.4097-11.79441.2545.245
100.54540.6465-0.39360.70050.10010.5652-0.1988-0.05930.15080.11650.48260.5341-0.0021-0.342100.62570.0217-0.03890.601-0.03640.7212-22.4407-12.6653-0.0595
111.0336-0.7795-0.28430.6377-0.21710.3956-0.00930.10850.5213-0.11190.09310.513-0.1842-0.2561-00.6063-0.0296-0.05870.5222-0.01760.5686-15.909211.08055.4979
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 142 through 178)
2X-RAY DIFFRACTION2chain 'A' and (resid 195 through 208 )
3X-RAY DIFFRACTION3chain 'A' and (resid 209 through 239 )
4X-RAY DIFFRACTION4chain 'A' and (resid 240 through 388 )
5X-RAY DIFFRACTION5chain 'A' and (resid 389 through 458 )
6X-RAY DIFFRACTION6chain 'B' and (resid 142 through 161 )
7X-RAY DIFFRACTION7chain 'B' and (resid 162 through 209 )
8X-RAY DIFFRACTION8chain 'B' and (resid 210 through 239 )
9X-RAY DIFFRACTION9chain 'B' and (resid 240 through 358 )
10X-RAY DIFFRACTION10chain 'B' and (resid 359 through 388 )
11X-RAY DIFFRACTION11chain 'B' and (resid 389 through 460 )

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