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

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Basic information

Entry
Database: PDB / ID: 8svx
TitleCrystal structure of the L428V mutant of pregnane X receptor ligand binding domain in complex with SJPYT-331
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: 2.14 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)80,8345
Polymers79,7632
Non-polymers1,0713
Water1,58588
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Dimer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1870 Å2
ΔGint-11 kcal/mol
Surface area26280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.036, 89.264, 105.713
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-WU6 / methyl 3-{[(1P)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carbonyl]amino}-4-{[(3S)-hexan-3-yl]oxy}benzoate


Mass: 496.555 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H32N4O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / 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


Mass: 18.015 Da / Num. of mol.: 88 / Source method: isolated from a natural source / 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: 2.52 Å3/Da / Density % sol: 51.09 % / 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: Feb 5, 2023
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.14→89.26 Å / Num. obs: 43922 / % possible obs: 97.4 % / Redundancy: 11.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.06 / Rpim(I) all: 0.017 / Rrim(I) all: 0.062 / Χ2: 0.78 / Net I/σ(I): 19.6 / Num. measured all: 502346
Reflection shellResolution: 2.14→2.2 Å / % possible obs: 83.3 % / Redundancy: 5.4 % / Rmerge(I) obs: 0.645 / Num. measured all: 16225 / Num. unique obs: 3029 / CC1/2: 0.759 / Rpim(I) all: 0.299 / Rrim(I) all: 0.715 / Χ2: 0.47 / Net I/σ(I) obs: 1.6

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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: 2.14→44.89 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 24.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2349 2212 5.04 %Random selection
Rwork0.2072 ---
obs0.2086 43858 97.29 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.14→44.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4540 0 76 88 4704
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024727
X-RAY DIFFRACTIONf_angle_d0.4946387
X-RAY DIFFRACTIONf_dihedral_angle_d13.1581710
X-RAY DIFFRACTIONf_chiral_restr0.032708
X-RAY DIFFRACTIONf_plane_restr0.004808
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.14-2.190.37291100.37182159X-RAY DIFFRACTION82
2.19-2.240.321100.30472333X-RAY DIFFRACTION87
2.24-2.290.30591160.25322439X-RAY DIFFRACTION93
2.29-2.360.22891300.22632557X-RAY DIFFRACTION96
2.36-2.420.2451440.22462614X-RAY DIFFRACTION99
2.42-2.50.23241490.22032623X-RAY DIFFRACTION100
2.5-2.590.27381360.22852628X-RAY DIFFRACTION100
2.59-2.70.24931260.23162679X-RAY DIFFRACTION100
2.7-2.820.30931570.26332634X-RAY DIFFRACTION100
2.82-2.970.30491410.25772667X-RAY DIFFRACTION100
2.97-3.150.24211490.23442679X-RAY DIFFRACTION100
3.15-3.40.26571400.22632668X-RAY DIFFRACTION100
3.4-3.740.20591160.20432716X-RAY DIFFRACTION100
3.74-4.280.20671300.18032721X-RAY DIFFRACTION100
4.28-5.390.19411800.17522697X-RAY DIFFRACTION100
5.39-44.890.2451780.18682832X-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)
12.731-0.0715-0.16484.2283-1.52093.5306-0.23680.2690.4134-0.27240.02060.1179-0.44970.34330.09540.3752-0.0366-0.00180.3031-0.03880.4082-28.853125.8667-34.8235
25.51070.22820.09951.9052-0.05513.56650.1783-0.6528-0.96760.1771-0.13080.44540.73870.0767-0.11710.70810.0359-0.06850.650.22560.8149-22.83155.9117-18.0796
32.99390.4310.17771.02240.56053.32670.0009-0.1151-0.17660.0741-0.02270.1150.2589-0.08210.0210.3755-0.0171-0.01350.30960.01880.4193-34.040717.6567-31.9834
41.83221.54231.85364.59750.82271.8601-0.34680.22530.1796-0.49790.06770.482-0.1943-0.17140.22680.4536-0.0273-0.11310.40990.04920.4464-44.058119.6974-47.9379
50.90.01981.68991.4339-0.27247.57870.3427-0.3983-0.28940.31520.20530.34360.795-0.4579-0.31540.5591-0.06160.00770.51150.0210.5246-40.607210.5073-28.2889
63.1744-1.89550.96642.35360.04743.045-0.0002-0.55610.02120.34190.16290.32710.0426-0.2322-0.16270.5693-0.0395-0.00260.6181-0.08090.5035-38.599625.5395-16.0824
73.5418-0.66570.63944.2539-2.12033.7252-0.1477-0.504-0.33160.39820.15910.4048-0.1996-0.33330.01570.40020.0037-0.00830.5153-0.07580.35575.76-1.7951.585
80.19410.0005-0.04840.0551-0.0090.00330.37281.04710.7922-0.2382-0.1615-0.4827-0.58642.0965-0.18821.2166-0.03640.12621.71190.24311.054113.460115.386-24.8155
93.4663-1.10181.76093.09681.71412.8185-0.33170.24480.1858-0.33570.47270.39970.20680.7185-0.22720.58690.0946-0.04350.82570.20180.5764-3.59379.8252-20.2571
104.1079-0.48330.57252.50870.10531.38880.0590.23740.1888-0.17-0.0091-0.0429-0.0258-0.0529-0.08940.4081-0.0023-0.00050.40670.03310.34089.40873.5264-6.7067
113.1165-0.92390.2712.49470.77812.4540.05840.0669-0.0006-0.26040.0323-0.2385-0.09170.2602-0.12140.40810.01810.00870.47920.00670.425216.8868-3.2885-5.8558
122.7044-2.1614-1.76652.9315-0.20592.9774-0.189-0.4394-0.29710.18320.2684-0.38330.26170.2445-0.03420.3890.0697-0.04550.47020.07740.481522.6786-12.14790.3307
132.6046-1.4777-0.05826.411-2.02931.63050.30690.51440.7788-0.6048-0.479-0.0882-0.38060.48990.08590.5754-0.0067-0.03470.50950.08680.6419.68524.8417-12.226
143.2716-1.32220.57472.47440.17035.58950.0614-0.130.82920.0195-0.1349-0.0912-0.78250.06650.1090.7052-0.012-0.06130.3971-0.03910.613812.090517.2991.3121
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 142 through 195 )
2X-RAY DIFFRACTION2chain 'A' and (resid 196 through 239 )
3X-RAY DIFFRACTION3chain 'A' and (resid 240 through 358 )
4X-RAY DIFFRACTION4chain 'A' and (resid 359 through 388 )
5X-RAY DIFFRACTION5chain 'A' and (resid 389 through 417 )
6X-RAY DIFFRACTION6chain 'A' and (resid 418 through 458 )
7X-RAY DIFFRACTION7chain 'B' and (resid 142 through 196 )
8X-RAY DIFFRACTION8chain 'B' and (resid 197 through 209 )
9X-RAY DIFFRACTION9chain 'B' and (resid 210 through 239 )
10X-RAY DIFFRACTION10chain 'B' and (resid 240 through 321 )
11X-RAY DIFFRACTION11chain 'B' and (resid 322 through 358 )
12X-RAY DIFFRACTION12chain 'B' and (resid 359 through 388 )
13X-RAY DIFFRACTION13chain 'B' and (resid 389 through 417 )
14X-RAY DIFFRACTION14chain 'B' and (resid 418 through 461 )

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