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- PDB-6xp9: STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUN... -

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Basic information

Entry
Database: PDB / ID: 6xp9
TitleSTRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUND TETHERED WITH SRC co-activator peptide IN COMPLEX WITH (S,S)-1
ComponentsNuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1 fusion
KeywordsNUCLEAR PROTEIN / NUCLEAR RECEPTOR / MULTIPLE BINDING MODES / XENOBIOTIC / PROMISCUOUS / LIGAND / NUCLEAR HORMONE RECEPTOR
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 / cellular response to Thyroglobulin triiodothyronine / estrous cycle / 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
Chem-QCG / 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: 2.27 Å
AuthorsKhan, J.A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Structure-based amelioration of PXR transactivation in a novel series of macrocyclic allosteric inhibitors of HIV-1 integrase.
Authors: Sivaprakasam, P. / Wang, Z. / Meanwell, N.A. / Khan, J.A. / Langley, D.R. / Johnson, S.R. / Li, G. / Pendri, A. / Connolly, T.P. / Gao, M. / Camac, D.M. / Klakouski, C. / Zvyaga, T. / ...Authors: Sivaprakasam, P. / Wang, Z. / Meanwell, N.A. / Khan, J.A. / Langley, D.R. / Johnson, S.R. / Li, G. / Pendri, A. / Connolly, T.P. / Gao, M. / Camac, D.M. / Klakouski, C. / Zvyaga, T. / Cianci, C. / McAuliffe, B. / Ding, B. / Discotto, L. / Krystal, M.R. / Jenkins, S. / Peese, K.M. / Narasimhulu Naidu, B.
History
DepositionJul 8, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 23, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.classification

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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
B: Nuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1 fusion
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,8905
Polymers79,7912
Non-polymers1,0993
Water3,027168
1
A: Nuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1 fusion
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,3992
Polymers39,8961
Non-polymers5041
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Nuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1 fusion
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,4913
Polymers39,8961
Non-polymers5962
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.029, 88.613, 105.860
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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 / 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
Fragment: Ligand Binding Domain tethered with SRC co-activator peptide
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1I2, PXR, NCOA1, BHLHE74, SRC1 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: O75469, UniProt: Q15788, histone acetyltransferase
#2: Chemical ChemComp-QCG / (2S)-tert-butoxy[7-(8-fluoro-5-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl]acetic acid


Mass: 503.565 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H30FN3O4 / Feature type: SUBJECT OF INVESTIGATION
#3: 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
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 168 / 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: 2.5 Å3/Da / Density % sol: 50.78 %
Crystal growTemperature: 296 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Ammonium acetate, 0.1 M Sodium HEPES pH 7.5, 18-20 % w/v PEG 4000.Crystals were cryoprotected by supplementing the mother liquor with 20% (v/v) Glycerol and harvested by flash-cooling in liquid nitrogen
PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 23, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.27→44.94 Å / Num. obs: 37683 / % possible obs: 99.9 % / Redundancy: 6.6 % / Biso Wilson estimate: 54.72 Å2 / Rmerge(I) obs: 0.126 / Net I/σ(I): 9.1
Reflection shellResolution: 2.27→2.39 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.53 / Mean I/σ(I) obs: 3 / Num. unique obs: 5391 / % possible all: 99.9

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (17-DEC-2019)refinement
PDB_EXTRACT3.25data extraction
SCALAdata scaling
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6BNS

6bns


Resolution: 2.27→44.94 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.212 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.214 / SU Rfree Blow DPI: 0.172 / SU Rfree Cruickshank DPI: 0.172
RfactorNum. reflection% reflectionSelection details
Rfree0.2199 1879 4.99 %RANDOM
Rwork0.1949 ---
obs0.1962 37627 99.9 %-
Displacement parametersBiso max: 121.98 Å2 / Biso mean: 60.68 Å2 / Biso min: 30.48 Å2
Baniso -1Baniso -2Baniso -3
1--0.3944 Å20 Å20 Å2
2---1.3528 Å20 Å2
3---1.7472 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 2.27→44.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4196 0 80 168 4444
Biso mean--69.3 62.02 -
Num. residues----531
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1519SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes808HARMONIC5
X-RAY DIFFRACTIONt_it4401HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion574SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3518SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4461HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg6089HARMONIC20.82
X-RAY DIFFRACTIONt_omega_torsion2.69
X-RAY DIFFRACTIONt_other_torsion16.78
LS refinement shellResolution: 2.27→2.29 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2026 47 6.24 %
Rwork0.1936 706 -
all0.1942 753 -
obs--100 %
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)
12.7130.47720.6542.6695-0.24814.55210.0813-0.2317-0.00960.1093-0.05710.27960.1937-0.2097-0.0242-0.2098-0.0284-0.0313-0.1627-0.0023-0.1588-34.306418.109-30.556
23.4111-1.2022-0.12923.6206-0.29262.46380.04860.00910.35910.04420.0365-0.1992-0.32080.0942-0.0851-0.13360.00390.0025-0.12020.0039-0.191511.57082.2046-5.713
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A142 - 459
2X-RAY DIFFRACTION2{ B|* }B142 - 462

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