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- PDB-3dcu: FXR with SRC1 and GSK8062 -

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Basic information

Entry
Database: PDB / ID: 3dcu
TitleFXR with SRC1 and GSK8062
Components
  • Bile acid receptor
  • Nuclear receptor coactivator 1
KeywordsTRANSCRIPTION/TRANSCRIPTION ACTIVATOR / FXR / nuclear receptor / GW4064 / alpha-helical sandwich / Activator / Alternative splicing / DNA-binding / Metal-binding / Nucleus / Receptor / Repressor / Transcription regulation / Zinc / Zinc-finger / Acyltransferase / Chromosomal rearrangement / Phosphoprotein / Polymorphism / Proto-oncogene / Transferase / Ubl conjugation / TRANSCRIPTION-TRANSCRIPTION ACTIVATOR COMPLEX
Function / homology
Function and homology information


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 ...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 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 / bile acid metabolic process / nitrogen catabolite activation of transcription from RNA polymerase II promoter / labyrinthine layer morphogenesis / regulation of thyroid hormone mediated signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / cell-cell junction assembly / positive regulation of female receptivity / regulation of cholesterol metabolic process / bile acid binding / bile acid signaling pathway / negative regulation of interleukin-2 production / cellular response to fatty acid / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / positive regulation of interleukin-17 production / positive regulation of insulin secretion involved in cellular response to glucose stimulus / intracellular glucose homeostasis / negative regulation of interleukin-6 production / estrous cycle / negative regulation of type II interferon production / cellular response to Thyroglobulin triiodothyronine / negative regulation of tumor necrosis factor production / 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 / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / response to retinoic acid / negative regulation of canonical NF-kappaB signal transduction / positive regulation of insulin receptor signaling pathway / histone acetyltransferase activity / Recycling of bile acids and salts / regulation of cellular response to insulin stimulus / histone acetyltransferase / Notch signaling pathway / cellular response to hormone stimulus / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / positive regulation of neuron differentiation / RORA activates gene expression / lactation / Regulation of lipid metabolism by PPARalpha / cerebellum development / cholesterol homeostasis / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / Activation of gene expression by SREBF (SREBP) / response to progesterone / nuclear estrogen receptor binding / transcription coregulator binding / nuclear receptor binding / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / euchromatin / SUMOylation of intracellular receptors / Heme signaling / mRNA transcription by RNA polymerase II / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / cerebral cortex development / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / male gonad development / nuclear receptor activity / Circadian Clock / response to estradiol / HATs acetylate histones / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / cellular response to lipopolysaccharide / transcription regulator complex / sequence-specific DNA binding / transcription by RNA polymerase II / cell differentiation
Similarity search - Function
Bile acid receptor, ligand binding domain / Thyroid hormone receptor / 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 ...Bile acid receptor, ligand binding domain / Thyroid hormone receptor / 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-O62 / 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
AuthorsWilliams, S.P. / Madauss, K.P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064.
Authors: Akwabi-Ameyaw, A. / Bass, J.Y. / Caldwell, R.D. / Caravella, J.A. / Chen, L. / Creech, K.L. / Deaton, D.N. / Jones, S.A. / Kaldor, I. / Liu, Y. / Madauss, K.P. / Marr, H.B. / McFadyen, R.B. ...Authors: Akwabi-Ameyaw, A. / Bass, J.Y. / Caldwell, R.D. / Caravella, J.A. / Chen, L. / Creech, K.L. / Deaton, D.N. / Jones, S.A. / Kaldor, I. / Liu, Y. / Madauss, K.P. / Marr, H.B. / McFadyen, R.B. / Miller, A.B. / III, F.N. / Parks, D.J. / Spearing, P.K. / Todd, D. / Williams, S.P. / Wisely, G.B.
History
DepositionJun 4, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 12, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.3Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,6923
Polymers30,1602
Non-polymers5321
Water905
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area840 Å2
ΔGint-9 kcal/mol
Surface area11280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)158.625, 158.625, 158.625
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number196
Space group name H-MF23

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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: 27509.604 Da / Num. of mol.: 1 / Fragment: Ligand binding domain, UNP residues 258-486
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H4, BAR, FXR, HRR1, RIP14 / Plasmid: pRSETA / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q96RI1
#2: Protein/peptide Nuclear receptor coactivator 1 / / Steroid receptor coactivator 1 / SRC-1


Mass: 2650.017 Da / Num. of mol.: 1 / Fragment: UNP residues 741-761 / Source method: obtained synthetically / Details: Synthetic / References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-O62 / 6-(4-{[3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazol-4-yl]methoxy}phenyl)naphthalene-1-carboxylic acid


Mass: 532.414 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H23Cl2NO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 5 / 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: 2.82 Å3/Da / Density % sol: 56.43 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.2M Li2SO4, 0.1M Bis-Tris pH6.5, 25% PEG3350, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jun 15, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
Reflection twinType: hemihedral / Operator: k,h,-l / Fraction: 0.177
ReflectionResolution: 2.9→50 Å / Num. obs: 7500 / % possible obs: 100 % / Redundancy: 7.4 % / Rmerge(I) obs: 0.071 / Χ2: 0.851 / Net I/σ(I): 9.6
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.9-37.20.5487400.583100
3-3.127.50.3787500.652100
3.12-3.277.50.2747370.712100
3.27-3.447.50.1867370.763100
3.44-3.657.50.1337540.826100
3.65-3.947.40.0887300.942100
3.94-4.337.40.0647621.054100
4.33-4.967.40.0517491.082100
4.96-6.247.40.0517560.929100
6.24-5070.037850.95599.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement
PDB_EXTRACT3.005data extraction
ADSCQuantumdata collection
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ID 3DCT

3dct


Resolution: 2.95→30 Å / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 56 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.228 470 6.6 %Random
Rwork0.181 ---
obs-6949 98.1 %-
Displacement parametersBiso mean: 62.697 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.95→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1845 0 37 5 1887
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.198
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2dna-rna_rep.param
X-RAY DIFFRACTION3water_rep.param
X-RAY DIFFRACTION4ion.param
X-RAY DIFFRACTION5O62.par

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