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- PDB-6a5z: Crystal structure of human FXR/RXR-LBD heterodimer bound to HNC18... -

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Basic information

Entry
Database: PDB / ID: 6a5z
TitleCrystal structure of human FXR/RXR-LBD heterodimer bound to HNC180 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


chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of ammonia assimilation cycle / regulation of low-density lipoprotein particle clearance / : / cellular response to bile acid / intracellular triglyceride homeostasis / urea metabolic process / negative regulation of interleukin-1 production / retinoic acid-responsive element binding ...chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of ammonia assimilation cycle / regulation of low-density lipoprotein particle clearance / : / cellular response to bile acid / intracellular triglyceride homeostasis / urea metabolic process / negative regulation of interleukin-1 production / retinoic acid-responsive element binding / negative regulation of very-low-density lipoprotein particle remodeling / NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose / NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis / positive regulation of thyroid hormone receptor signaling pathway / regulation of insulin secretion involved in cellular response to glucose stimulus / regulation of bile acid biosynthetic process / NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / negative regulation of monocyte chemotactic protein-1 production / toll-like receptor 9 signaling pathway / Carnitine shuttle / nuclear receptor-mediated bile acid signaling pathway / bile acid nuclear receptor activity / retinoic acid binding / bile acid binding / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / cellular response to fatty acid / positive regulation of vitamin D receptor signaling pathway / cell-cell junction assembly / TGFBR3 expression / nuclear vitamin D receptor binding / Signaling by Retinoic Acid / regulation of cholesterol metabolic process / positive regulation of interleukin-17 production / negative regulation of interleukin-2 production / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / DNA binding domain binding / positive regulation of lipid metabolic process / hypothalamus development / positive regulation of bone mineralization / negative regulation of interleukin-6 production / LBD domain binding / male mating behavior / nuclear steroid receptor activity / positive regulation of lipoprotein transport / cell maturation / negative regulation of type II interferon production / progesterone receptor signaling pathway / response to progesterone / Synthesis of bile acids and bile salts / monocyte differentiation / regulation of lipid metabolic process / negative regulation of tumor necrosis factor production / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / positive regulation of cholesterol efflux / cerebellum development / fatty acid homeostasis / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / cellular response to low-density lipoprotein particle stimulus / response to retinoic acid / positive regulation of insulin receptor signaling pathway / protein-lysine-acetyltransferase activity / negative regulation of tumor necrosis factor-mediated signaling pathway / nuclear retinoid X receptor binding / lactation / estrous cycle / positive regulation of neuron differentiation / retinoic acid receptor signaling pathway / estrogen receptor signaling pathway / Recycling of bile acids and salts / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / histone acetyltransferase / hormone-mediated signaling pathway / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / cellular response to hormone stimulus / intracellular receptor signaling pathway / peroxisome proliferator activated receptor signaling pathway / Regulation of lipid metabolism by PPARalpha / positive regulation of adipose tissue development / bile acid and bile salt transport / cholesterol homeostasis / peptide binding / BMAL1:CLOCK,NPAS2 activates circadian expression / male gonad development / regulation of cellular response to insulin stimulus / RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / Expression of BMAL (ARNTL), CLOCK, and NPAS2 / intracellular glucose homeostasis / hippocampus development / nuclear estrogen receptor binding / nuclear receptor binding / negative regulation of canonical NF-kappaB signal transduction / transcription coregulator binding / positive regulation of insulin secretion involved in cellular response to glucose stimulus / RNA polymerase II transcription regulatory region sequence-specific DNA binding / 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 ...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 / 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
(9cis)-retinoic acid / Chem-9R3 / 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: 2.95 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
D: Retinoic acid receptor RXR-alpha
H: Bile acid receptor
L: Retinoic acid receptor RXR-alpha
E: Nuclear receptor coactivator 1
F: Nuclear receptor coactivator 1
G: Nuclear receptor coactivator 1
I: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,43612
Polymers114,6668
Non-polymers1,7704
Water30617
1
A: Bile acid receptor
D: Retinoic acid receptor RXR-alpha
E: Nuclear receptor coactivator 1
F: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,2186
Polymers57,3334
Non-polymers8852
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
H: Bile acid receptor
L: Retinoic acid receptor RXR-alpha
G: Nuclear receptor coactivator 1
I: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,2186
Polymers57,3334
Non-polymers8852
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.530, 96.130, 114.240
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 4 molecules AHDL

#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.: 2 / 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
#2: 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.: 2 / Fragment: ligand binding domain
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, 4 molecules EFGI

#3: Protein/peptide
Nuclear receptor coactivator 1


Mass: 1905.186 Da / Num. of mol.: 4 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: B5MCN7, UniProt: Q15788*PLUS

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Non-polymers , 3 types, 21 molecules

#4: Chemical ChemComp-9R3 / 2-[(1R,5S)-9-[[3-[2,6-bis(chloranyl)phenyl]-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-3-azabicyclo[3.3.1]nonan-3-yl]-1,3-benzothiazole-6-carboxylic acid


Mass: 584.513 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H27Cl2N3O4S
#5: Chemical ChemComp-9CR / (9cis)-retinoic acid


Mass: 300.435 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H28O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / 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: 2.14 Å3/Da / Density % sol: 42.62 % / Mosaicity: 0.5 °
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 0.2 M Ammonium iodide, 20% w/v Polyethylene glycol 3,350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.9778 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 17, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9778 Å / Relative weight: 1
ReflectionResolution: 2.95→89.53 Å / Num. obs: 20868 / % possible obs: 98 % / Redundancy: 3.5 % / CC1/2: 0.955 / Rmerge(I) obs: 0.182 / Rpim(I) all: 0.11 / Rrim(I) all: 0.214 / Net I/σ(I): 5.4 / Num. measured all: 73288 / Scaling rejects: 301
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
2.95-3.133.60.5751212733400.7220.3380.671298.8
8.85-89.533.20.11827218520.9360.0780.14311.397

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.5.32data scaling
MOLREPphasing
REFMAC5.8.0158refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.95→73.55 Å / Cor.coef. Fo:Fc: 0.91 / Cor.coef. Fo:Fc free: 0.869 / WRfactor Rfree: 0.2686 / WRfactor Rwork: 0.2182 / FOM work R set: 0.7716 / SU B: 24.785 / SU ML: 0.45 / SU Rfree: 0.5273 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.527 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.282 1069 5.1 %RANDOM
Rwork0.2214 ---
obs0.2245 19737 97.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 147.33 Å2 / Biso mean: 53.765 Å2 / Biso min: 20.03 Å2
Baniso -1Baniso -2Baniso -3
1-1.65 Å20 Å20 Å2
2--1.53 Å2-0 Å2
3----3.18 Å2
Refinement stepCycle: final / Resolution: 2.95→73.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7371 0 122 17 7510
Biso mean--43.81 29.69 -
Num. residues----910
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0197655
X-RAY DIFFRACTIONr_bond_other_d0.0020.027294
X-RAY DIFFRACTIONr_angle_refined_deg1.5261.99410340
X-RAY DIFFRACTIONr_angle_other_deg1.035316934
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8475898
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.37324.302358
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.967151414
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2411548
X-RAY DIFFRACTIONr_chiral_restr0.0720.21169
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0218227
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021479
LS refinement shellResolution: 2.95→3.027 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.331 85 -
Rwork0.317 1455 -
all-1540 -
obs--98.97 %

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