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- PDB-5y1j: Crystal structure of human FXR in complex with a functional drug ... -

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Basic information

Entry
Database: PDB / ID: 5y1j
TitleCrystal structure of human FXR in complex with a functional drug ligand
Components
  • Bile acid receptor
  • Peptide from Nuclear receptor coactivator 2
KeywordsNUCLEAR PROTEIN / Complex
Function / homology
Function and homology information


regulation of urea metabolic process / 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 / negative regulation of very-low-density lipoprotein particle remodeling / negative regulation of interleukin-1 production ...regulation of urea metabolic process / 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 / negative regulation of very-low-density lipoprotein particle remodeling / negative regulation of interleukin-1 production / nuclear receptor-mediated bile acid signaling pathway / regulation of bile acid biosynthetic process / regulation of insulin secretion involved in cellular response to glucose stimulus / : / toll-like receptor 9 signaling pathway / negative regulation of monocyte chemotactic protein-1 production / bile acid nuclear receptor activity / bile acid metabolic process / cell-cell junction assembly / bile acid binding / cellular response to fatty acid / regulation of cholesterol metabolic process / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / negative regulation of interleukin-2 production / intracellular glucose homeostasis / locomotor rhythm / positive regulation of interleukin-17 production / positive regulation of insulin secretion involved in cellular response to glucose stimulus / aryl hydrocarbon receptor binding / negative regulation of interleukin-6 production / negative regulation of type II interferon production / regulation of lipid metabolic process / cellular response to Thyroglobulin triiodothyronine / negative regulation of tumor necrosis factor production / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / negative regulation of tumor necrosis factor-mediated signaling pathway / fatty acid homeostasis / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear retinoid X receptor binding / negative regulation of canonical NF-kappaB signal transduction / positive regulation of insulin receptor signaling pathway / Recycling of bile acids and salts / cellular response to hormone stimulus / Notch signaling pathway / positive regulation of adipose tissue development / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / Regulation of lipid metabolism by PPARalpha / regulation of cellular response to insulin stimulus / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / cholesterol homeostasis / nuclear receptor coactivator activity / transcription coregulator binding / response to progesterone / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / circadian regulation of gene expression / SUMOylation of intracellular receptors / Heme signaling / mRNA transcription by RNA polymerase II / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Transcriptional activation of mitochondrial biogenesis / euchromatin / PPARA activates gene expression / Cytoprotection by HMOX1 / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / nuclear receptor activity / Circadian Clock / HATs acetylate histones / cellular response to lipopolysaccharide / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / transcription regulator complex / sequence-specific DNA binding / transcription by RNA polymerase II / transcription coactivator activity / cell differentiation / receptor complex / nuclear body / protein dimerization activity / transcription cis-regulatory region binding / DNA-binding transcription factor activity, RNA polymerase II-specific / defense response to bacterium / inflammatory response / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein domain specific binding / innate immune response / chromatin binding / regulation of DNA-templated transcription / chromatin / negative regulation of apoptotic process
Similarity search - Function
Bile acid receptor, ligand binding domain / Thyroid hormone receptor / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / 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 ...Bile acid receptor, ligand binding domain / Thyroid hormone receptor / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / 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 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 / 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-D5H / Nuclear receptor coactivator 2 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / SAD / Resolution: 2 Å
AuthorsLu, Y. / Li, Y.
CitationJournal: To Be Published
Title: Crystal structure of human FXR in complex with a functional drug liagnd
Authors: Lu, Y. / Li, Y.
History
DepositionJul 20, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 31, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 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
U: Peptide from Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1853
Polymers27,8302
Non-polymers3551
Water1,982110
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1000 Å2
ΔGint-5 kcal/mol
Surface area11580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)34.668, 162.046, 115.619
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

#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: 26609.609 Da / Num. of mol.: 1 / Fragment: UNP residues 244-471
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H4, BAR, FXR, HRR1, RIP14 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q96RI1
#2: Protein/peptide Peptide from Nuclear receptor coactivator 2 / NCoA-2 / Class E basic helix-loop-helix protein 75 / bHLHe75 / Transcriptional intermediary factor 2 / hTIF2


Mass: 1220.462 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-D5H / 2-[[2-fluoranyl-4-(3-methoxyphenyl)phenyl]carbamoyl]cyclopentene-1-carboxylic acid / Vidofludimus, 2-[[2-fluoro-4-(3-methoxyphenyl)phenyl]carbamoyl]cyclopentene-1-carboxylic acid


Mass: 355.360 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H18FNO4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 110 / 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: 2.94 Å3/Da / Density % sol: 58.21 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / Details: 0.1M MgSO4, 25% w/v polyethylene glycol 8000

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Data collection

DiffractionMean temperature: 293.15 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.987 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Dec 25, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 22538 / % possible obs: 100 % / Redundancy: 13.2 % / Rmerge(I) obs: 0.097 / Rpim(I) all: 0.028 / Rrim(I) all: 0.101 / Χ2: 1.041 / Net I/σ(I): 7.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2-2.0313.70.4130.9650.1160.4291.102100
2.03-2.0713.70.3490.9780.0980.3631.096100
2.07-2.1113.60.3030.9750.0850.3151.111100
2.11-2.1513.50.2670.9810.0750.2771.156100
2.15-2.213.30.2350.9830.0670.2441.122100
2.2-2.25130.210.9870.060.2181.166100
2.25-2.3112.50.1870.9870.0550.1951.163100
2.31-2.3713.50.1740.990.0490.1811.107100
2.37-2.4413.70.1630.9880.0460.1691.143100
2.44-2.5213.60.1530.9930.0430.1591.111100
2.52-2.6113.40.1380.9930.0390.1431.104100
2.61-2.7113.10.1280.9930.0370.1331.079100
2.71-2.8412.40.1190.9920.0350.1241.06100
2.84-2.9913.60.1120.9930.0320.1161.056100
2.99-3.1713.60.1050.9950.0290.1091.013100
3.17-3.4213.30.0930.9960.0260.0960.94100
3.42-3.7612.40.0890.9960.0260.0930.925100
3.76-4.3113.60.0840.9970.0240.0870.878100
4.31-5.4312.50.0810.9960.0240.0850.82399.9
5.43-10120.0680.9930.0210.0720.664100

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.8.0073refinement
PDB_EXTRACT3.22data extraction
PHENIXmodel building
REFMACrefinement
RefinementMethod to determine structure: SAD / Resolution: 2→50 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.922 / SU B: 3.506 / SU ML: 0.098 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.156 / ESU R Free: 0.15
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2378 1091 4.8 %RANDOM
Rwork0.1938 ---
obs0.1958 21488 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 89.81 Å2 / Biso mean: 25.751 Å2 / Biso min: 11.28 Å2
Baniso -1Baniso -2Baniso -3
1-0.14 Å2-0 Å20 Å2
2--0.08 Å20 Å2
3----0.22 Å2
Refinement stepCycle: final / Resolution: 2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1938 0 26 110 2074
Biso mean--20.99 33.66 -
Num. residues----236
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0250.0192005
X-RAY DIFFRACTIONr_bond_other_d0.0020.021942
X-RAY DIFFRACTIONr_angle_refined_deg3.2481.9822706
X-RAY DIFFRACTIONr_angle_other_deg1.09634476
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7425233
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.60424.89898
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.66615375
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.8731510
X-RAY DIFFRACTIONr_chiral_restr0.1270.2301
X-RAY DIFFRACTIONr_gen_planes_refined0.010.022215
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02453
LS refinement shellResolution: 2.001→2.053 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.26 62 -
Rwork0.225 1545 -
all-1607 -
obs--98.89 %

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