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- PDB-6hty: PXR in complex with P2X4 inhibitor compound 25 -

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Basic information

Entry
Database: PDB / ID: 6hty
TitlePXR in complex with P2X4 inhibitor compound 25
ComponentsNuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1
KeywordsTRANSCRIPTION / PXR / SRC-1 / CYP3A4 Induction
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 / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / male mating behavior / hypothalamus development ...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 / 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 / protein-lysine-acetyltransferase activity / 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 transport / estrous cycle / xenobiotic catabolic process / nuclear retinoid X receptor binding / RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / Expression of BMAL (ARNTL), CLOCK, and NPAS2 / Recycling of bile acids and salts / histone acetyltransferase / cellular response to hormone stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / estrogen receptor signaling pathway / intracellular 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 / Heme signaling / PPARA activates gene expression / Transcriptional activation of mitochondrial biogenesis / Cytoprotection by HMOX1 / cerebral cortex development / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / mRNA transcription by RNA polymerase II / 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 / transcription coactivator activity / cell differentiation / 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 / positive regulation of DNA-templated transcription / chromatin / 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 / Retinoid X Receptor / Retinoid X Receptor / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-GRH / 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: 2.22 Å
AuthorsHillig, R.C. / Puetter, V. / Werner, S. / Mesch, S. / Laux-Biehlmann, A. / Braeuer, N. / Dahloef, H. / Klint, J. / ter Laak, A. / Pook, E. ...Hillig, R.C. / Puetter, V. / Werner, S. / Mesch, S. / Laux-Biehlmann, A. / Braeuer, N. / Dahloef, H. / Klint, J. / ter Laak, A. / Pook, E. / Neagoe, I. / Nubbemeyer, R. / Schulz, S.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Discovery and Characterization of the Potent and Selective P2X4 InhibitorN-[4-(3-Chlorophenoxy)-3-sulfamoylphenyl]-2-phenylacetamide (BAY-1797) and Structure-Guided Amelioration of Its CYP3A4 Induction Profile.
Authors: Werner, S. / Mesch, S. / Hillig, R.C. / Ter Laak, A. / Klint, J. / Neagoe, I. / Laux-Biehlmann, A. / Dahllof, H. / Brauer, N. / Puetter, V. / Nubbemeyer, R. / Schulz, S. / Bairlein, M. / ...Authors: Werner, S. / Mesch, S. / Hillig, R.C. / Ter Laak, A. / Klint, J. / Neagoe, I. / Laux-Biehlmann, A. / Dahllof, H. / Brauer, N. / Puetter, V. / Nubbemeyer, R. / Schulz, S. / Bairlein, M. / Zollner, T.M. / Steinmeyer, A.
History
DepositionOct 5, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 4, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 8, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Jan 24, 2024Group: 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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


Theoretical massNumber of molelcules
Total (without water)79,2829
Polymers78,3682
Non-polymers9147
Water2,666148
1
A: Nuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,5115
Polymers39,1841
Non-polymers3264
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Nuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,7714
Polymers39,1841
Non-polymers5873
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)85.417, 88.616, 104.929
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: GLY / Beg label comp-ID: GLY / End auth comp-ID: SER / End label comp-ID: SER / Refine code: _ / Auth seq-ID: 142 - 460 / Label seq-ID: 24 - 342

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein Nuclear receptor subfamily 1 group I member 2,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: 39184.035 Da / Num. of mol.: 2 / Mutation: K129G,K129G
Source method: isolated from a genetically manipulated source
Details: FRAGMENT: PXR, RESIDUES 129-434, K129G is a cloning artifact; LINKER; SRC-1, RESIDUES 678-700
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1I2, PXR, NCOA1, BHLHE74, SRC1 / Production host: Escherichia coli (E. coli)
References: UniProt: O75469, UniProt: Q15788, histone acetyltransferase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-GRH / (2~{R})-~{N}-[4-(3-chloranylphenoxy)-3-sulfamoyl-phenyl]-2-phenyl-propanamide


Mass: 430.905 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H19ClN2O4S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 148 / Source method: isolated from a natural source / Formula: H2O

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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: 2.54 Å3/Da / Density % sol: 51.52 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 1 microliter protein at 12.1 mg/ml (in 20 millimolar Tris pH 7.8, 250 millimolar NaCl, 2.5 millimolar EDTA, 5% (v/v) glycerol, 5 mM DTT), preincubated with 10 millimolar compound 15 (from ...Details: 1 microliter protein at 12.1 mg/ml (in 20 millimolar Tris pH 7.8, 250 millimolar NaCl, 2.5 millimolar EDTA, 5% (v/v) glycerol, 5 mM DTT), preincubated with 10 millimolar compound 15 (from 200 millimolar stock in DMSO), mixed with 1 microliter of reservoir (100 mM imidazole pH 8.0, 17 % (v/v) MPD). Crystals additionally soaked in 20 millimolar compound 15 prior to data collection. cryo buffer 34% (v/v) MPD supplemented with 20 millimolar compound 15

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 1.040432 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 1, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.040432 Å / Relative weight: 1
ReflectionResolution: 2.22→45.15 Å / Num. obs: 39804 / % possible obs: 99.3 % / Redundancy: 5 % / Biso Wilson estimate: 57.6 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.065 / Net I/σ(I): 15.4
Reflection shellResolution: 2.22→2.35 Å / Redundancy: 4.9 % / Mean I/σ(I) obs: 1.7 / Num. unique obs: 6262 / CC1/2: 0.707 / Rrim(I) all: 0.847 / % possible all: 98.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
XDSdata reduction
XDSdata scaling
REFMAC5.8.0049phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3HVL

3hvl


Resolution: 2.22→45.15 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.942 / SU B: 13.093 / SU ML: 0.153 / Cross valid method: THROUGHOUT / ESU R: 0.23 / ESU R Free: 0.189 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22611 1991 5 %RANDOM
Rwork0.1847 ---
obs0.18674 37812 99.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 69.232 Å2
Baniso -1Baniso -2Baniso -3
1--1.43 Å2-0 Å20 Å2
2--1.01 Å2-0 Å2
3---0.42 Å2
Refinement stepCycle: 1 / Resolution: 2.22→45.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4869 0 55 148 5072
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0195156
X-RAY DIFFRACTIONr_bond_other_d0.0010.024841
X-RAY DIFFRACTIONr_angle_refined_deg1.421.9726961
X-RAY DIFFRACTIONr_angle_other_deg0.973.00111239
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.45629
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.9123.633245
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.92415959
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5421537
X-RAY DIFFRACTIONr_chiral_restr0.080.2759
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0215645
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021070
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it4.6834.3662445
X-RAY DIFFRACTIONr_mcbond_other4.6774.3662444
X-RAY DIFFRACTIONr_mcangle_it7.1989.7753061
X-RAY DIFFRACTIONr_mcangle_other7.1989.7783062
X-RAY DIFFRACTIONr_scbond_it5.7864.8592711
X-RAY DIFFRACTIONr_scbond_other5.7864.862712
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.70910.6163888
X-RAY DIFFRACTIONr_long_range_B_refined12.04252.5875715
X-RAY DIFFRACTIONr_long_range_B_other12.05252.4485690
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 19266 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.1 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.219→2.277 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.335 143 -
Rwork0.293 2711 -
obs--97.97 %
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)
13.1002-0.4322-0.77281.9740.48893.74610.0270.36950.0912-0.1612-0.14380.126-0.4198-0.17260.11670.05760.0182-0.00910.0853-0.00640.09518.70328.62229.909
24.11250.7602-0.17673.0285-0.26652.04580.0423-0.2182-0.30450.1668-0.012-0.10350.18510.0052-0.03030.031-0.007-0.00530.08430.00750.03854.92541.8217.948
310.6980.1265-3.47015.49170.60176.48740.04310.5465-0.40240.0267-0.05440.0770.5881-0.42130.01140.1778-0.01030.02180.2794-0.17770.26712.4112.26918.433
49.49991.26311.40885.6842-1.271312.9077-0.0861-0.207-0.6453-0.15640.2443-0.60880.69820.4529-0.15820.2701-0.02120.07860.1567-0.14660.246856.29327.039-7.36
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A138 - 434
2X-RAY DIFFRACTION2B138 - 434
3X-RAY DIFFRACTION3A442 - 461
4X-RAY DIFFRACTION4B442 - 461

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