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- PDB-4wvd: Identification of a novel FXR ligand that regulates metabolism -

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Basic information

Entry
Database: PDB / ID: 4wvd
TitleIdentification of a novel FXR ligand that regulates metabolism
Components
  • Bile acid receptor
  • Nuclear receptor corepressor 1
KeywordsTRANSCRIPTION / AF-2 helix / ligand binding pocket / three-layer helical sandwich / TRANSCRIPTION REGULATOR FXR / BAR / NR1H4 / bile acid receptor / NHR / nuclear receptor / corepressor / Transcription regulation
Function / homology
Function and homology information


NR1D1 (REV-ERBA) represses gene expression / Loss of MECP2 binding ability to the NCoR/SMRT complex / 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 ...NR1D1 (REV-ERBA) represses gene expression / Loss of MECP2 binding ability to the NCoR/SMRT complex / 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 / negative regulation of androgen receptor signaling pathway / negative regulation of interleukin-1 production / regulation of bile acid biosynthetic process / regulation of insulin secretion involved in cellular response to glucose stimulus / cellular response to organonitrogen compound / toll-like receptor 9 signaling pathway / negative regulation of monocyte chemotactic protein-1 production / intracellular receptor signaling pathway / negative regulation of JNK cascade / bile acid metabolic process / nitrogen catabolite activation of transcription from RNA polymerase II promoter / negative regulation of glycolytic process / bile acid binding / cell-cell junction assembly / bile acid signaling pathway / nuclear thyroid hormone receptor binding / negative regulation of interleukin-2 production / cellular response to fatty acid / regulation of cholesterol metabolic process / negative regulation of fatty acid metabolic process / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / Notch-HLH transcription pathway / positive regulation of interleukin-17 production / intracellular glucose homeostasis / locomotor rhythm / positive regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of interleukin-6 production / histone deacetylase complex / Regulation of MECP2 expression and activity / negative regulation of type II interferon production / negative regulation of tumor necrosis factor production / Synthesis of bile acids and bile salts / negative regulation of tumor necrosis factor-mediated signaling pathway / spindle assembly / 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 / Nuclear signaling by ERBB4 / Recycling of bile acids and salts / Notch signaling pathway / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / positive regulation of adipose tissue development / transcription repressor complex / Regulation of lipid metabolism by PPARalpha / negative regulation of miRNA transcription / cholesterol homeostasis / HDACs deacetylate histones / transcription coregulator binding / nuclear receptor binding / Downregulation of SMAD2/3:SMAD4 transcriptional activity / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Heme signaling / SUMOylation of intracellular receptors / euchromatin / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / mitotic spindle / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / Nuclear Receptor transcription pathway / transcription corepressor activity / nuclear receptor activity / Circadian Clock / chromatin organization / DNA-binding transcription activator activity, RNA polymerase II-specific / cellular response to lipopolysaccharide / RNA polymerase II-specific DNA-binding transcription factor binding / sequence-specific DNA binding / transcription by RNA polymerase II / cell differentiation / receptor complex / transcription cis-regulatory region binding / DNA-binding transcription factor activity, RNA polymerase II-specific / defense response to bacterium / inflammatory response / RNA polymerase II cis-regulatory region sequence-specific DNA binding
Similarity search - Function
N-CoR, GPS2-interacting domain / G-protein pathway suppressor 2-interacting domain / Bile acid receptor, ligand binding domain / Thyroid hormone receptor / SANT domain profile. / SANT domain / Myb domain / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain ...N-CoR, GPS2-interacting domain / G-protein pathway suppressor 2-interacting domain / Bile acid receptor, ligand binding domain / Thyroid hormone receptor / SANT domain profile. / SANT domain / Myb domain / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / Retinoid X Receptor / Retinoid X Receptor / Homeobox-like 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
FORMIC ACID / Chem-IVM / Nuclear receptor corepressor 1 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsWang, R. / Li, Y.
Funding support China, 4items
OrganizationGrant numberCountry
National Basic Research Program of China973 Program: 2012CB910104 China
National Natural Science Foundation of China81273567 China
National Natural Science Foundation of China31270776 China
Programme of Introducing Talents of Discipline to UniversitiesB12001 China
CitationJournal: Nat Commun / Year: 2013
Title: The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism.
Authors: Jin, L. / Feng, X. / Rong, H. / Pan, Z. / Inaba, Y. / Qiu, L. / Zheng, W. / Lin, S. / Wang, R. / Wang, Z. / Wang, S. / Liu, H. / Li, S. / Xie, W. / Li, Y.
History
DepositionNov 5, 2014Deposition site: RCSB / Processing site: PDBJ
SupersessionFeb 11, 2015ID: 4II6
Revision 1.0Feb 11, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 2, 2015Group: Data collection
Revision 1.2Sep 27, 2017Group: Data collection / Derived calculations / Category: diffrn_detector / pdbx_struct_oper_list
Item: _diffrn_detector.detector / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Mar 20, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Nuclear receptor corepressor 1
A: Bile acid receptor
D: Nuclear receptor corepressor 1
B: Bile acid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,05914
Polymers52,9414
Non-polymers2,11810
Water19811
1
C: Nuclear receptor corepressor 1
A: Bile acid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,5307
Polymers26,4702
Non-polymers1,0595
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1150 Å2
ΔGint-11 kcal/mol
Surface area12470 Å2
MethodPISA
2
D: Nuclear receptor corepressor 1
B: Bile acid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,5307
Polymers26,4702
Non-polymers1,0595
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1090 Å2
ΔGint-11 kcal/mol
Surface area12180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.008, 161.759, 169.018
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number24
Space group name H-MI212121
Components on special symmetry positions
IDModelComponents
11A-601-

HOH

Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.998958, -0.037084, -0.026618), (0.032136, -0.157183, -0.987046), (0.03242, -0.986873, 0.158211)-14.3448, -40.819679, -34.91283
3given(1), (1), (1)
4given(-0.993996, -0.098282, -0.048084), (0.061121, -0.134271, -0.989058), (0.090751, -0.986059, 0.139472)-14.90824, -40.129929, -33.526199
Detailsbiological unit is a dimer. There are 2 biological units in the asymmetric unit (chains A & B and chains C & D)

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Components

#1: Protein/peptide Nuclear receptor corepressor 1 / N-CoR1


Mass: 1866.189 Da / Num. of mol.: 2 / Fragment: UNP residues 2259-2275 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: O75376
#2: 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: 24604.262 Da / Num. of mol.: 2 / Fragment: Ligand Binding Domain, UNP residues 244-454
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H4, BAR, FXR, HRR1, RIP14 / Plasmid: pET24 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q96RI1
#3: Chemical
ChemComp-FMT / FORMIC ACID / Formic acid


Mass: 46.025 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: CH2O2
#4: Chemical ChemComp-IVM / (2aE,4E,5'S,6S,6'R,7S,8E,11R,13R,15S,17aR,20R,20aR,20bS)-6'-[(2S)-butan-2-yl]-20,20b-dihydroxy-5',6,8,19-tetramethyl-17 -oxo-3',4',5',6,6',10,11,14,15,17,17a,20,20a,20b-tetradecahydro-2H,7H-spiro[11,15-methanofuro[4,3,2-pq][2,6]benzodioxacy clooctadecine-13,2'-pyran]-7-yl 2,6-dideoxy-4-O-(2,6-dideoxy-3-O-methyl-alpha-L-arabino-hexopyranosyl)-3-O-methyl-alpha-L-arabino-hexopyranoside / 22,23-DIHYDROAVERMECTIN B1A / IVERMECTIN / Ivermectin


Mass: 875.093 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C48H74O14 / Comment: antiparasitic*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 11 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHIS SEQUENCE CORRESPONDS TO THE ISOFORM 4 FOUND IN UNP 075376.

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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: 3.51 Å3/Da / Density % sol: 64.98 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 50mM HEPES pH7.0, 3.5M sodium formate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 1.005 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 9, 2012
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.005 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 20898 / % possible obs: 64.1 % / Redundancy: 7.5 % / Rmerge(I) obs: 0.104 / Net I/σ(I): 10.4
Reflection shellResolution: 2.3→2.34 Å / Redundancy: 1 % / Rmerge(I) obs: 0.77

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
HKL-2000data scaling
Cootmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→50 Å / Cor.coef. Fo:Fc: 0.878 / Cor.coef. Fo:Fc free: 0.872 / SU B: 17.293 / SU ML: 0.345 / Cross valid method: THROUGHOUT / ESU R: 1.28 / ESU R Free: 0.427 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.30221 819 5 %RANDOM
Rwork0.27741 ---
obs0.27872 15531 98.27 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 75.502 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å20 Å20 Å2
2---0.12 Å2-0 Å2
3---0.1 Å2
Refinement stepCycle: LAST / Resolution: 2.9→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3484 0 148 11 3643
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0193562
X-RAY DIFFRACTIONr_bond_other_d0.0060.023334
X-RAY DIFFRACTIONr_angle_refined_deg1.731.9694809
X-RAY DIFFRACTIONr_angle_other_deg1.04337652
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3785445
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.28525.247162
X-RAY DIFFRACTIONr_dihedral_angle_3_deg23.30415607
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9871514
X-RAY DIFFRACTIONr_chiral_restr0.0880.2556
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214044
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02796
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_it5.9667.8241798
X-RAY DIFFRACTIONr_mcbond_other5.9647.821799
X-RAY DIFFRACTIONr_mcangle_it8.94611.7242237
X-RAY DIFFRACTIONr_mcangle_other8.94611.7252238
X-RAY DIFFRACTIONr_scbond_it8.6858.0881762
X-RAY DIFFRACTIONr_scbond_other8.6928.0971749
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other11.83911.9612572
X-RAY DIFFRACTIONr_long_range_B_refined13.61263.1924220
X-RAY DIFFRACTIONr_long_range_B_other13.61863.1994215
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.352 53 -
Rwork0.281 1048 -
obs--90.62 %

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