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- PDB-6a5y: Crystal structure of human FXR/RXR-LBD heterodimer bound to HNC14... -

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Basic information

Entry
Database: PDB / ID: 6a5y
TitleCrystal structure of human FXR/RXR-LBD heterodimer bound to HNC143 and 9cRA and SRC1
Components
  • Bile acid receptor
  • Nuclear receptor coactivator 1
  • Retinoic acid receptor RXR-alpha
KeywordsTRANSCRIPTION / nuclear receptor / heterodimer / complex
Function / homology
Function and homology information


regulation of urea metabolic process / intracellular bile acid receptor signaling pathway / chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of glutamate metabolic process / positive regulation of ammonia assimilation cycle / bile acid receptor activity / regulation of low-density lipoprotein particle clearance / intracellular triglyceride homeostasis / cellular response to bile acid ...regulation of urea metabolic process / intracellular bile acid receptor signaling pathway / chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of glutamate metabolic process / positive regulation of ammonia assimilation cycle / bile acid receptor activity / regulation of low-density lipoprotein particle clearance / intracellular triglyceride homeostasis / cellular response to bile acid / negative regulation of very-low-density lipoprotein particle remodeling / positive regulation of transporter activity / negative regulation of interleukin-1 production / retinoic acid-responsive element binding / NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis / NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose / NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake / positive regulation of thyroid hormone mediated signaling pathway / regulation of bile acid biosynthetic process / regulation of insulin secretion involved in cellular response to glucose stimulus / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / cellular response to organonitrogen compound / toll-like receptor 9 signaling pathway / negative regulation of monocyte chemotactic protein-1 production / intracellular receptor signaling pathway / Carnitine metabolism / bile acid metabolic process / anatomical structure development / ion binding / nitrogen catabolite activation of transcription from RNA polymerase II promoter / Regulation of pyruvate dehydrogenase (PDH) complex / retinoic acid binding / labyrinthine layer morphogenesis / regulation of thyroid hormone mediated signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of vitamin D receptor signaling pathway / nuclear vitamin D receptor binding / cell-cell junction assembly / positive regulation of female receptivity / regulation of cholesterol metabolic process / bile acid binding / bile acid signaling pathway / negative regulation of interleukin-2 production / cellular response to fatty acid / Signaling by Retinoic Acid / hypothalamus development / DNA binding domain binding / nuclear steroid receptor activity / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / LBD domain binding / positive regulation of interleukin-17 production / positive regulation of insulin secretion involved in cellular response to glucose stimulus / intracellular glucose homeostasis / negative regulation of interleukin-6 production / estrous cycle / positive regulation of cholesterol efflux / negative regulation of type II interferon production / cellular response to Thyroglobulin triiodothyronine / negative regulation of tumor necrosis factor production / Synthesis of bile acids and bile salts / negative regulation of tumor necrosis factor-mediated signaling pathway / fatty acid homeostasis / retinoic acid receptor signaling pathway / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / positive regulation of bone mineralization / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear retinoid X receptor binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / response to retinoic acid / negative regulation of canonical NF-kappaB signal transduction / positive regulation of insulin receptor signaling pathway / histone acetyltransferase activity / Recycling of bile acids and salts / regulation of cellular response to insulin stimulus / histone acetyltransferase / Notch signaling pathway / cellular response to hormone stimulus / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / positive regulation of neuron differentiation / lactation / Regulation of lipid metabolism by PPARalpha / cerebellum development / hormone-mediated signaling pathway / cholesterol homeostasis / BMAL1:CLOCK,NPAS2 activates circadian gene expression / nuclear receptor coactivator activity / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / response to progesterone / nuclear estrogen receptor binding / transcription coregulator binding / nuclear receptor binding / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / peptide binding / euchromatin
Similarity search - Function
Bile acid receptor, ligand binding domain / Nuclear/hormone receptor activator site AF-1 / Nuclear/hormone receptor activator site AF-1 / Thyroid hormone receptor / Retinoid X receptor/HNF4 / 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 ...Bile acid receptor, ligand binding domain / Nuclear/hormone receptor activator site AF-1 / Nuclear/hormone receptor activator site AF-1 / Thyroid hormone receptor / Retinoid X receptor/HNF4 / 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 / Retinoid X Receptor / Retinoid X Receptor / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
(9cis)-retinoic acid / Chem-9R0 / PHOSPHATE ION / Nuclear receptor coactivator 1 / Retinoic acid receptor RXR-alpha / Nuclear receptor coactivator 1 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsWang, N. / Liu, J.
Funding support China, 1items
OrganizationGrant numberCountry
31770817 China
CitationJournal: J. Biol. Chem. / Year: 2018
Title: Ligand binding and heterodimerization with retinoid X receptor alpha (RXR alpha ) induce farnesoid X receptor (FXR) conformational changes affecting coactivator binding
Authors: Wang, N. / Zou, Q. / Xu, J. / Zhang, J. / Liu, J.
History
DepositionJun 25, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 10, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 17, 2018Group: Data collection / Database references / Structure summary
Category: citation / citation_author / entity
Item: _citation.journal_abbrev / _citation.pdbx_database_id_DOI ..._citation.journal_abbrev / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _entity.formula_weight
Revision 1.2Dec 5, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.3Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bile acid receptor
B: Nuclear receptor coactivator 1
D: Retinoic acid receptor RXR-alpha
F: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,3639
Polymers57,2054
Non-polymers1,1585
Water1,45981
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5010 Å2
ΔGint-54 kcal/mol
Surface area20330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.380, 83.380, 161.630
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

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Protein , 2 types, 2 molecules AD

#1: Protein Bile acid receptor / Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Nuclear receptor subfamily 1 group H ...Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Nuclear receptor subfamily 1 group H member 4 / Retinoid X receptor-interacting protein 14 / RXR-interacting protein 14


Mass: 26726.600 Da / Num. of mol.: 1 / Fragment: ligand binding domain / Mutation: C432E, C466E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H4, BAR, FXR, HRR1, RIP14 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta2(DE3) / References: UniProt: Q96RI1
#3: Protein Retinoic acid receptor RXR-alpha / Nuclear receptor subfamily 2 group B member 1 / Retinoid X receptor alpha


Mass: 26667.857 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RXRA, NR2B1 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta2(DE3) / References: UniProt: P19793

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Protein/peptide , 1 types, 2 molecules BF

#2: Protein/peptide Nuclear receptor coactivator 1 /


Mass: 1905.186 Da / Num. of mol.: 2 / Fragment: ligand binding domain / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: B5MCN7, UniProt: Q15788*PLUS

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Non-polymers , 5 types, 86 molecules

#4: Chemical ChemComp-9R0 / 2-[2-[[3-[2,6-bis(chloranyl)phenyl]-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-6-azaspiro[3.4]octan-6-yl]-1,3-benzothiazole-6-carboxylic acid


Mass: 570.487 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C28H25Cl2N3O4S
#5: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-9CR / (9cis)-retinoic acid / Alitretinoin


Mass: 300.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H28O2 / Comment: anticancer, antineoplastic*YM
#7: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 81 / 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: 2.49 Å3/Da / Density % sol: 50.61 % / Mosaicity: 0.49 °
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 5.6
Details: 0.2M Ammonium sulfate , 0.1M tri-sodium citrate,25%PEG 4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.9785 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jan 5, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9785 Å / Relative weight: 1
ReflectionResolution: 2.1→83.38 Å / Num. obs: 34177 / % possible obs: 100 % / Redundancy: 13.1 % / CC1/2: 0.999 / Rmerge(I) obs: 0.085 / Rpim(I) all: 0.024 / Rrim(I) all: 0.089 / Net I/σ(I): 18.9 / Num. measured all: 448159 / Scaling rejects: 1391
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs
2.1-2.1613.50.8843747227710.8450.2470.9193.4
8.91-83.389.50.03652845590.9980.0120.03842.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
Aimless0.5.29data scaling
MOLREPphasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→74.1 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.941 / WRfactor Rfree: 0.2584 / WRfactor Rwork: 0.1929 / FOM work R set: 0.8151 / SU B: 5.402 / SU ML: 0.142 / SU R Cruickshank DPI: 0.2045 / SU Rfree: 0.1792 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.204 / ESU R Free: 0.179 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.241 1665 4.9 %RANDOM
Rwork0.1975 ---
obs0.1997 32442 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 120.62 Å2 / Biso mean: 42.375 Å2 / Biso min: 19.75 Å2
Baniso -1Baniso -2Baniso -3
1-0.15 Å2-0 Å2-0 Å2
2--0.15 Å2-0 Å2
3----0.3 Å2
Refinement stepCycle: final / Resolution: 2.1→74.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3746 0 75 81 3902
Biso mean--50.06 39.31 -
Num. residues----462
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0193930
X-RAY DIFFRACTIONr_bond_other_d0.0020.023751
X-RAY DIFFRACTIONr_angle_refined_deg1.7991.9775315
X-RAY DIFFRACTIONr_angle_other_deg1.0792.988712
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9995464
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.26123.81189
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.59415732
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.431526
X-RAY DIFFRACTIONr_chiral_restr0.1210.2598
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0214235
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02763
LS refinement shellResolution: 2.1→2.155 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.349 122 -
Rwork0.267 2356 -
all-2478 -
obs--100 %

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