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- PDB-6a60: Crystal structure of human FXR/RXR-LBD heterodimer bound to GW406... -

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Basic information

Entry
Database: PDB / ID: 6a60
TitleCrystal structure of human FXR/RXR-LBD heterodimer bound to GW4064 and 9cRA and SRC1
Components
  • Bile acid receptor
  • Nuclear receptor coactivator 1
  • Retinoic acid receptor RXR-alpha
KeywordsTRANSCRIPTION / Nuclear receptor heterodimer
Function / homology
Function and homology information


regulation of urea metabolic process / nuclear receptor-mediated bile acid signaling pathway / chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of glutamate metabolic process / positive regulation of ammonia assimilation cycle / : / regulation of low-density lipoprotein particle clearance / intracellular triglyceride homeostasis / cellular response to bile acid ...regulation of urea metabolic process / nuclear receptor-mediated bile acid signaling pathway / chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of glutamate metabolic process / positive regulation of ammonia assimilation cycle / : / regulation of low-density lipoprotein particle clearance / intracellular triglyceride homeostasis / cellular response to bile acid / positive regulation of transporter activity / negative regulation of very-low-density lipoprotein particle remodeling / 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 receptor 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 / intracellular receptor signaling pathway / negative regulation of monocyte chemotactic protein-1 production / Carnitine metabolism / ion binding / bile acid metabolic process / nitrogen catabolite activation of transcription from RNA polymerase II promoter / Regulation of pyruvate dehydrogenase (PDH) complex / retinoic acid binding / labyrinthine layer morphogenesis / positive regulation of vitamin D receptor signaling pathway / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / nuclear vitamin D receptor binding / bile acid binding / cell-cell junction assembly / positive regulation of female receptivity / bile acid signaling pathway / cellular response to fatty acid / negative regulation of interleukin-2 production / Signaling by Retinoic Acid / DNA binding domain binding / regulation of cholesterol metabolic process / nuclear steroid receptor activity / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / LBD domain binding / positive regulation of interleukin-17 production / intracellular glucose homeostasis / positive regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of interleukin-6 production / negative regulation of type II interferon production / negative regulation of tumor necrosis factor production / cellular response to Thyroglobulin triiodothyronine / negative regulation of tumor necrosis factor-mediated signaling pathway / estrous cycle / Synthesis of bile acids and bile salts / positive regulation of cholesterol efflux / retinoic acid receptor signaling pathway / fatty acid homeostasis / 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 / positive regulation of insulin receptor signaling pathway / response to retinoic acid / negative regulation of canonical NF-kappaB signal transduction / histone acetyltransferase activity / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / histone acetyltransferase / Notch signaling pathway / 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 / hormone-mediated signaling pathway / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / transcription coregulator binding / response to progesterone / cholesterol homeostasis / hippocampus development / nuclear receptor binding / nuclear estrogen receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / peptide binding / Heme signaling / SUMOylation of intracellular receptors
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
Chem-064 / (9cis)-retinoic acid / 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: 3.05 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

Downloads & links

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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)58,1766
Polymers57,3334
Non-polymers8432
Water181
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)102.849, 102.849, 109.456
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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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: 26854.730 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) / 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 , 3 types, 3 molecules

#4: Chemical ChemComp-064 / 3-[(E)-2-(2-chloro-4-{[3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazol-4-yl]methoxy}phenyl)ethenyl]benzoic acid


Mass: 542.838 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H22Cl3NO4
#5: Chemical ChemComp-9CR / (9cis)-retinoic acid


Mass: 300.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H28O2 / Comment: anticancer, antineoplastic*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 2.52 Å3/Da / Density % sol: 51.27 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7 / Details: 0.1 M Sodium acetate trihydrate, 12% PEG3350

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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: Nov 19, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9785 Å / Relative weight: 1
ReflectionResolution: 3.05→102.85 Å / Num. obs: 11678 / % possible obs: 99.8 % / Redundancy: 13.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.071 / Rpim(I) all: 0.02 / Rrim(I) all: 0.074 / Net I/σ(I): 19.4 / Num. measured all: 160717 / Scaling rejects: 1306
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
3.05-3.2614.41.0152950020540.8460.2741.052399.7
8.63-102.8511.30.02867685990.9990.0090.02961.399.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
Aimless0.5.32data scaling
MOLREPphasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.05→74.95 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.937 / WRfactor Rfree: 0.2746 / WRfactor Rwork: 0.2104 / FOM work R set: 0.7548 / SU B: 24.502 / SU ML: 0.425 / SU Rfree: 0.5203 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.52 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2883 521 4.5 %RANDOM
Rwork0.2253 ---
obs0.2282 11002 98.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 287.87 Å2 / Biso mean: 123.249 Å2 / Biso min: 55.05 Å2
Baniso -1Baniso -2Baniso -3
1--1.79 Å2-0 Å20 Å2
2---1.79 Å20 Å2
3---3.57 Å2
Refinement stepCycle: final / Resolution: 3.05→74.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3638 0 58 1 3697
Biso mean--118.25 94.39 -
Num. residues----448
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0143768
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173513
X-RAY DIFFRACTIONr_angle_refined_deg1.7321.6655084
X-RAY DIFFRACTIONr_angle_other_deg1.0291.6368220
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8065441
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.25322.01209
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.60115701
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.291524
X-RAY DIFFRACTIONr_chiral_restr0.1020.2482
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.024122
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02670
LS refinement shellResolution: 3.05→3.129 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.411 37 -
Rwork0.34 808 -
all-845 -
obs--99.06 %

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