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- PDB-3oki: Crystal structure of human FXR in complex with (2S)-2-[2-(4-chlor... -

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Basic information

Entry
Database: PDB / ID: 3oki
TitleCrystal structure of human FXR in complex with (2S)-2-[2-(4-chlorophenyl)-1H-benzimidazol-1-yl]-N,2-dicyclohexylethanamide
Components
  • Bile acid receptor
  • peptide of Nuclear receptor coactivator 1
KeywordsHORMONE RECEPTOR / NUCLEAR RECEPTOR / CHOLESTEROL / BILE ACID / DNA-BINDING / NUCLEUS / RECEPTOR / TRANSCRIPTION / LIGAND BINDING DOMAIN TRANSCRIPTION REGULATION / COACTIVATOR / FXR ALTERNATIVE SPLICING
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-OKI / Nuclear receptor coactivator 1 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsRudolph, M.G.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia & diabetes
Authors: Richter, H.G.F. / Benson, G.M. / Blum, D. / Chaput, E. / Feng, S. / Gardes, C. / Grether, U. / Hartman, P. / Kuhn, B. / Martin, R.E. / Plancher, J.-M. / Rudolph, M.G. / Schuler, F. / Taylor, S. / Bleicher, K.H.
History
DepositionAug 25, 2010Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Dec 29, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bile acid receptor
B: peptide of Nuclear receptor coactivator 1
C: Bile acid receptor
D: peptide of Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,6806
Polymers57,7804
Non-polymers9002
Water72140
1
A: Bile acid receptor
B: peptide of Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,3403
Polymers28,8902
Non-polymers4501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1120 Å2
ΔGint-6 kcal/mol
Surface area12530 Å2
MethodPISA
2
C: Bile acid receptor
D: peptide of Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,3403
Polymers28,8902
Non-polymers4501
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1140 Å2
ΔGint-8 kcal/mol
Surface area12320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.215, 84.528, 190.240
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Bile acid receptor / fxr / Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Nuclear receptor subfamily 1 group ...fxr / 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: 27100.191 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 258-486 / Mutation: E281A, E354A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H4, HCG_20893 / Plasmid: PET28A / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q96RI1
#2: Protein/peptide peptide of Nuclear receptor coactivator 1 / NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal ...NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal carcinoma antigen NY-REN-52 / Steroid receptor coactivator 1 / SRC-1


Mass: 1790.026 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 744-757 / Source method: obtained synthetically / Details: THIS SEQUENCE OCCURS NATURALLY IN HUMANS / References: UniProt: Q15788
#3: Chemical ChemComp-OKI / (2S)-2-[2-(4-chlorophenyl)-1H-benzimidazol-1-yl]-N,2-dicyclohexylethanamide


Mass: 450.015 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H32ClN3O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 40 / 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: 2.51 Å3/Da / Density % sol: 51.04 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1M Bis-Tris pH 6.5, 28% PEG 2000, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9721 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 27, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9721 Å / Relative weight: 1
ReflectionResolution: 2→36.03 Å / Num. obs: 30936 / % possible obs: 79.9 % / Redundancy: 4.2 % / Biso Wilson estimate: 47.79 Å2 / Net I/σ(I): 13.06
Reflection shellResolution: 2.02→2.12 Å / Redundancy: 3 % / % possible all: 73.5

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Processing

Software
NameVersionClassification
PHASERphasing
PHENIX(phenix.refine: 1.6.4_486)refinement
XDSdata reduction
SADABSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: INHOUSE

Resolution: 2→31.273 Å / SU ML: 0.28 / σ(F): 0 / Phase error: 37.22 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2799 1481 4.81 %
Rwork0.2463 --
obs0.248 30807 77.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 58.914 Å2 / ksol: 0.399 e/Å3
Displacement parametersBiso mean: 57.6081 Å2
Baniso -1Baniso -2Baniso -3
1--3.6375 Å20 Å2-0 Å2
2--5.8533 Å2-0 Å2
3----2.2157 Å2
Refinement stepCycle: LAST / Resolution: 2→31.273 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3960 0 64 40 4064
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024114
X-RAY DIFFRACTIONf_angle_d0.5135556
X-RAY DIFFRACTIONf_dihedral_angle_d14.9651552
X-RAY DIFFRACTIONf_chiral_restr0.037620
X-RAY DIFFRACTIONf_plane_restr0.002706
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.06450.4171990.38751943X-RAY DIFFRACTION57
2.0645-2.13830.40691070.33352372X-RAY DIFFRACTION70
2.1383-2.22390.4097890.33971933X-RAY DIFFRACTION68
2.2239-2.32510.2631220.3419643X-RAY DIFFRACTION21
2.3251-2.44760.37291750.3073215X-RAY DIFFRACTION96
2.4476-2.60090.35381600.28953351X-RAY DIFFRACTION98
2.6009-2.80160.33281850.27823372X-RAY DIFFRACTION99
2.8016-3.08330.3191690.27033443X-RAY DIFFRACTION100
3.0833-3.5290.32081580.2623433X-RAY DIFFRACTION99
3.529-4.44410.26251280.21392200X-RAY DIFFRACTION64
4.4441-31.27690.21681890.21043421X-RAY DIFFRACTION95

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