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- PDB-5wzx: Structural basis for a pentacyclic oleanane-type triterpenoid as ... -

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Basic information

Entry
Database: PDB / ID: 5wzx
TitleStructural basis for a pentacyclic oleanane-type triterpenoid as a ligand of FXR
Components
  • Bile acid receptor
  • SRC2-3 peptide from Nuclear receptor coactivator 2
KeywordsTRANSCRIPTION / FXR ligand
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-7VX / (R,R)-2,3-BUTANEDIOL / Nuclear receptor coactivator 2 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95 Å
AuthorsLu, Y. / Li, Y.
CitationJournal: Mol. Pharmacol. / Year: 2018
Title: Identification of an Oleanane-Type Triterpene Hedragonic Acid as a Novel Farnesoid X Receptor Ligand with Liver Protective Effects and Anti-inflammatory Activity
Authors: Lu, Y. / Zheng, W. / Lin, S. / Guo, F. / Zhu, Y. / Wei, Y. / Liu, X. / Jin, S. / Jin, L. / Li, Y.
History
DepositionJan 19, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 3, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year
Revision 1.2Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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: Bile acid receptor
C: SRC2-3 peptide from Nuclear receptor coactivator 2
D: SRC2-3 peptide from Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,4309
Polymers56,2794
Non-polymers1,1525
Water68538
1
A: Bile acid receptor
C: SRC2-3 peptide from Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,8506
Polymers28,1392
Non-polymers7114
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1390 Å2
ΔGint-2 kcal/mol
Surface area11760 Å2
MethodPISA
2
B: Bile acid receptor
D: SRC2-3 peptide from Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,5803
Polymers28,1392
Non-polymers4411
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1060 Å2
ΔGint-5 kcal/mol
Surface area11590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.561, 86.075, 177.300
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: 26674.658 Da / Num. of mol.: 2 / Fragment: UNP residues 258-485
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) / References: UniProt: Q96RI1
#2: Protein/peptide SRC2-3 peptide from Nuclear receptor coactivator 2


Mass: 1464.664 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-7VX / (4aR,6aR,6aS,6bS,8aS,9R,12aR,14bR)-2,2,6a,6b,9,12a-hexamethyl-10-oxidanylidene-1,3,4,5,6,6a,7,8,8a,9,11,12,13,14b-tetradecahydropicene-4a-carboxylic acid


Mass: 440.658 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H44O3
#4: Chemical ChemComp-BU3 / (R,R)-2,3-BUTANEDIOL


Mass: 90.121 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 38 / 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: 2.7 Å3/Da / Density % sol: 54.4 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop
Details: 0.1 M HEPES, 10% w/v Polyethylene glycol 6000, 5% v/v (+/-)-2-Methyl-2,4-pentanediol
PH range: 7.5

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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: IMAGE PLATE / Date: Oct 6, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.005 Å / Relative weight: 1
ReflectionResolution: 2.95→88.65 Å / Num. obs: 10710 / % possible obs: 86.5 % / Redundancy: 7.9 % / Net I/σ(I): 1.52

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMAC5.8.0135refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3dct

3dct


Resolution: 2.95→88.65 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.904 / SU B: 21.722 / SU ML: 0.376 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.504
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2625 514 4.8 %RANDOM
Rwork0.2082 ---
obs0.2108 10194 86.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 192.52 Å2 / Biso mean: 85.867 Å2 / Biso min: 41.71 Å2
Baniso -1Baniso -2Baniso -3
1--1.56 Å2-0 Å2-0 Å2
2--1.19 Å2-0 Å2
3---0.37 Å2
Refinement stepCycle: final / Resolution: 2.95→88.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3664 0 82 38 3784
Biso mean--106.42 65.77 -
Num. residues----445
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0193822
X-RAY DIFFRACTIONr_bond_other_d0.0030.023764
X-RAY DIFFRACTIONr_angle_refined_deg1.8392.0015180
X-RAY DIFFRACTIONr_angle_other_deg1.12138672
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.4115437
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.80324.837184
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.69215713
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.6011520
X-RAY DIFFRACTIONr_chiral_restr0.1020.2596
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214120
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02838
LS refinement shellResolution: 2.951→3.028 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.299 12 -
Rwork0.364 189 -
all-201 -
obs--22.16 %

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