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- PDB-3dct: FXR with SRC1 and GW4064 -

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Basic information

Entry
Database: PDB / ID: 3dct
TitleFXR with SRC1 and GW4064
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 / 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 / labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / cell-cell junction assembly / bile acid binding / positive regulation of female receptivity / cellular response to fatty acid / regulation of cholesterol metabolic process / negative regulation of interleukin-2 production / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / intracellular glucose homeostasis / positive regulation of interleukin-17 production / positive regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of interleukin-6 production / 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 / estrous cycle / 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 / progesterone receptor signaling pathway / nuclear retinoid X receptor binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / response to retinoic acid / positive regulation of insulin receptor signaling pathway / histone acetyltransferase activity / negative regulation of canonical NF-kappaB signal transduction / Recycling of bile acids and salts / histone acetyltransferase / cellular response to hormone stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / Notch signaling pathway / estrogen receptor signaling pathway / positive regulation of adipose tissue development / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / lactation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / regulation of cellular response to insulin stimulus / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian gene expression / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / cholesterol homeostasis / transcription coregulator binding / response to progesterone / nuclear receptor binding / nuclear estrogen receptor binding / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / SUMOylation of intracellular receptors / Heme signaling / mRNA transcription by RNA polymerase II / Transcriptional activation of mitochondrial biogenesis / euchromatin / 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 / nuclear receptor activity / male gonad development / Circadian Clock / response to estradiol / HATs acetylate histones / DNA-binding transcription activator activity, RNA polymerase II-specific / cellular response to lipopolysaccharide / Estrogen-dependent gene expression / sequence-specific DNA binding / transcription regulator complex / transcription by RNA polymerase II / transcription coactivator activity
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 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-064 / Nuclear receptor coactivator 1 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.5 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)30,7023
Polymers30,1602
Non-polymers5431
Water84747
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area890 Å2
ΔGint-9 kcal/mol
Surface area11270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)159.449, 159.449, 159.449
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-064 / 3-[(E)-2-(2-chloro-4-{[3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazol-4-yl]methoxy}phenyl)ethenyl]benzoic acid


Mass: 542.838 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H22Cl3NO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 47 / 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: 2.87 Å3/Da / Density % sol: 57.1 %
Crystal growTemperature: 298 K / Method: hanging drop / pH: 6.5
Details: 0.2M Li2SO4, 0.1M Bis-Tris pH6.5, 25% PEG3350, 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: MARRESEARCH / Detector: CCD / Date: Sep 15, 2001
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: 0.02
ReflectionResolution: 2.49→50 Å / Num. all: 13237 / Num. obs: 13236 / % possible obs: 99.9 % / Redundancy: 7 % / Biso Wilson estimate: 41.6 Å2 / Rmerge(I) obs: 0.084 / Rsym value: 0.084 / Net I/σ(I): 10.9
Reflection shellResolution: 2.49→2.59 Å / Redundancy: 7 % / Rmerge(I) obs: 0.48 / Mean I/σ(I) obs: 3.33 / Num. unique all: 1329 / % possible all: 100

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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
HKL-2000data collection
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB Entry 1A28

1a28


Resolution: 2.5→20 Å / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 1 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.24 817 7 %random
Rwork0.23 ---
obs-11714 99.9 %-
Displacement parametersBiso mean: 50.071 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.5→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1837 0 36 47 1920
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_deg1.234
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 DIFFRACTION5gw064.par

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