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- PDB-3oof: Crystal structure of human FXR in complex with 4-({(2S)-2-[2-(4-c... -

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Entry
Database: PDB / ID: 3oof
TitleCrystal structure of human FXR in complex with 4-({(2S)-2-[2-(4-chlorophenyl)-5,6-difluoro-1H-benzimidazol-1-yl]-2-cyclohexylacetyl}amino)benzoic acid
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


chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of ammonia assimilation cycle / regulation of low-density lipoprotein particle clearance / : / cellular response to bile acid / intracellular triglyceride homeostasis / urea metabolic process / negative regulation of interleukin-1 production / negative regulation of very-low-density lipoprotein particle remodeling ...chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of ammonia assimilation cycle / regulation of low-density lipoprotein particle clearance / : / cellular response to bile acid / intracellular triglyceride homeostasis / urea metabolic process / negative regulation of interleukin-1 production / negative regulation of very-low-density lipoprotein particle remodeling / regulation of insulin secretion involved in cellular response to glucose stimulus / regulation of bile acid biosynthetic process / negative regulation of monocyte chemotactic protein-1 production / toll-like receptor 9 signaling pathway / nuclear receptor-mediated bile acid signaling pathway / bile acid nuclear receptor activity / bile acid binding / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / cellular response to fatty acid / cell-cell junction assembly / regulation of cholesterol metabolic process / positive regulation of interleukin-17 production / negative regulation of interleukin-2 production / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / hypothalamus development / negative regulation of interleukin-6 production / male mating behavior / negative regulation of type II interferon production / progesterone receptor signaling pathway / response to progesterone / Synthesis of bile acids and bile salts / negative regulation of tumor necrosis factor production / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / cerebellum development / fatty acid homeostasis / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / response to retinoic acid / positive regulation of insulin receptor signaling pathway / protein-lysine-acetyltransferase activity / negative regulation of tumor necrosis factor-mediated signaling pathway / nuclear retinoid X receptor binding / lactation / positive regulation of neuron differentiation / estrous cycle / estrogen receptor signaling pathway / Recycling of bile acids and salts / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / histone acetyltransferase / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / cellular response to hormone stimulus / intracellular receptor signaling pathway / peroxisome proliferator activated receptor signaling pathway / Regulation of lipid metabolism by PPARalpha / positive regulation of adipose tissue development / bile acid and bile salt transport / cholesterol homeostasis / BMAL1:CLOCK,NPAS2 activates circadian expression / regulation of cellular response to insulin stimulus / male gonad development / RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / Expression of BMAL (ARNTL), CLOCK, and NPAS2 / intracellular glucose homeostasis / hippocampus development / nuclear estrogen receptor binding / nuclear receptor binding / negative regulation of canonical NF-kappaB signal transduction / transcription coregulator binding / positive regulation of insulin secretion involved in cellular response to glucose stimulus / RNA polymerase II transcription regulatory region sequence-specific DNA binding / SUMOylation of intracellular receptors / RNA polymerase II transcription regulator complex / Heme signaling / PPARA activates gene expression / Transcriptional activation of mitochondrial biogenesis / Cytoprotection by HMOX1 / cerebral cortex development / negative regulation of inflammatory response / euchromatin / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / mRNA transcription by RNA polymerase II / nuclear receptor activity / transcription coregulator activity / response to estradiol / transcription regulator complex / cellular response to lipopolysaccharide / HATs acetylate histones / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / sequence-specific DNA binding / DNA-binding transcription factor activity, RNA polymerase II-specific / cell differentiation / signaling receptor complex / transcription coactivator activity / defense response to bacterium
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 / Nuclear receptor coactivators bHLH domain / 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 / Double treble clef zinc finger, C4 type / 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-OOF / Nuclear receptor coactivator 1 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.29 Å
AuthorsRudolph, M.G.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties
Authors: Richter, H.G.F. / Benson, G.M. / Bleicher, K.H. / Blum, D. / Chaput, E. / Clemann, N. / Feng, S. / Gardes, C. / Grether, U. / Hartman, P. / Kuhn, B. / Martin, R.E. / Plancher, J.M. / ...Authors: Richter, H.G.F. / Benson, G.M. / Bleicher, K.H. / Blum, D. / Chaput, E. / Clemann, N. / Feng, S. / Gardes, C. / Grether, U. / Hartman, P. / Kuhn, B. / Martin, R.E. / Plancher, J.M. / Rudolph, M.G. / Schuler, F. / Taylor, S.
History
DepositionAug 31, 2010Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jan 19, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 26, 2014Group: Database references
Revision 1.3Nov 8, 2017Group: Refinement description / Category: software
Revision 1.4Mar 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 1.5Apr 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)58,8286
Polymers57,7804
Non-polymers1,0482
Water2,684149
1
A: Bile acid receptor
B: peptide of Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,4143
Polymers28,8902
Non-polymers5241
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-8 kcal/mol
Surface area12600 Å2
MethodPISA
2
C: Bile acid receptor
D: peptide of Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,4143
Polymers28,8902
Non-polymers5241
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1190 Å2
ΔGint-6 kcal/mol
Surface area12590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.580, 83.340, 190.420
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-OOF / 4-({(2S)-2-[2-(4-chlorophenyl)-5,6-difluoro-1H-benzimidazol-1-yl]-2-cyclohexylacetyl}amino)benzoic acid


Mass: 523.958 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H24ClF2N3O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 149 / 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: 2.46 Å3/Da / Density % sol: 49.95 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.1M Bis-Tris pH 5.5, 25% PEG 3350, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 28, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.29→47.6 Å / Num. obs: 25551 / % possible obs: 97.5 % / Redundancy: 5.99 % / Biso Wilson estimate: 43.52 Å2 / Rmerge(I) obs: 0.0733 / Rsym value: 0.0733 / Net I/σ(I): 13.99
Reflection shellResolution: 2.29→2.39 Å / Redundancy: 3.54 % / Rmerge(I) obs: 0.5799 / Mean I/σ(I) obs: 1.99 / Rsym value: 0.5799 / % possible all: 84.8

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Processing

Software
NameVersionClassification
PHASERphasing
BUSTER2.9.5refinement
XDS(VERSION December 6data reduction
SADABSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: INHOUSE

Resolution: 2.29→26.82 Å / Cor.coef. Fo:Fc: 0.9462 / Cor.coef. Fo:Fc free: 0.9127 / SU R Cruickshank DPI: 0.313 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.32 / SU Rfree Blow DPI: 0.24 / SU Rfree Cruickshank DPI: 0.24
RfactorNum. reflection% reflectionSelection details
Rfree0.2548 1271 4.99 %RANDOM
Rwork0.1954 ---
obs0.1985 25491 97.9 %-
Displacement parametersBiso mean: 48.03 Å2
Baniso -1Baniso -2Baniso -3
1-5.7788 Å20 Å20 Å2
2---7.7766 Å20 Å2
3---1.9978 Å2
Refine analyzeLuzzati coordinate error obs: 0.322 Å
Refinement stepCycle: LAST / Resolution: 2.29→26.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3981 0 74 149 4204
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1490SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes119HARMONIC2
X-RAY DIFFRACTIONt_gen_planes575HARMONIC5
X-RAY DIFFRACTIONt_it4145HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion531SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5028SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4145HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5602HARMONIC21.13
X-RAY DIFFRACTIONt_omega_torsion2.62
X-RAY DIFFRACTIONt_other_torsion20.09
LS refinement shellResolution: 2.29→2.38 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.4104 123 4.85 %
Rwork0.3753 2411 -
all0.3771 2534 -
obs--97.9 %

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