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- PDB-3l1b: Complex Structure of FXR Ligand-binding domain with a tetrahydroa... -

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Basic information

Entry
Database: PDB / ID: 3l1b
TitleComplex Structure of FXR Ligand-binding domain with a tetrahydroazepinoindole compound
ComponentsFarnesoid X receptor
KeywordsTRANSCRIPTION / Nuclear receptor / FXR agonist / FXR ligand-binding domain / Nucleus / Receptor / Transcription regulation
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 / regulation of bile acid biosynthetic process / regulation of insulin secretion involved in cellular response to glucose stimulus / 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 metabolic process / cell-cell junction assembly / bile acid binding / regulation of cholesterol metabolic process / cellular response to fatty acid / negative regulation of interleukin-2 production / bile acid and bile salt transport / positive regulation of interleukin-17 production / intracellular glucose homeostasis / negative regulation of interleukin-6 production / negative regulation of type II interferon production / positive regulation of insulin secretion involved in cellular response to glucose stimulus / Synthesis of bile acids and bile salts / negative regulation of tumor necrosis factor production / negative regulation of tumor necrosis factor-mediated signaling pathway / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / fatty acid homeostasis / positive regulation of insulin receptor signaling pathway / nuclear retinoid X receptor binding / Recycling of bile acids and salts / intracellular receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / positive regulation of adipose tissue development / Notch signaling pathway / cholesterol homeostasis / transcription coregulator binding / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / SUMOylation of intracellular receptors / euchromatin / PPARA activates gene expression / Nuclear Receptor transcription pathway / negative regulation of inflammatory response / RNA polymerase II transcription regulator complex / nuclear receptor activity / cellular response to lipopolysaccharide / DNA-binding transcription activator activity, RNA polymerase II-specific / sequence-specific DNA binding / transcription by RNA polymerase II / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / receptor complex / transcription cis-regulatory region binding / nuclear speck / defense response to bacterium / inflammatory response / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / innate immune response / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / chromatin / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
Bile acid receptor, ligand binding domain / Thyroid hormone receptor / : / Retinoid X Receptor / Retinoid X Receptor / 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. ...Bile acid receptor, ligand binding domain / Thyroid hormone receptor / : / Retinoid X Receptor / Retinoid X Receptor / 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-635 / Bile acid receptor / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsXu, W. / Lundquist, J.T.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Improvement of Physiochemical Properties of the Tetrahydroazepinoindole Series of Farnesoid X Receptor (FXR) Agonists: Beneficial Modulation of Lipids in Primates.
Authors: Lundquist, J.T. / Harnish, D.C. / Kim, C.Y. / Mehlmann, J.F. / Unwalla, R.J. / Phipps, K.M. / Crawley, M.L. / Commons, T. / Green, D.M. / Xu, W. / Hum, W.T. / Eta, J.E. / Feingold, I. / ...Authors: Lundquist, J.T. / Harnish, D.C. / Kim, C.Y. / Mehlmann, J.F. / Unwalla, R.J. / Phipps, K.M. / Crawley, M.L. / Commons, T. / Green, D.M. / Xu, W. / Hum, W.T. / Eta, J.E. / Feingold, I. / Patel, V. / Evans, M.J. / Lai, K. / Borges-Marcucci, L. / Mahaney, P.E. / Wrobel, J.E.
History
DepositionDec 11, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 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

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Assembly

Deposited unit
A: Farnesoid X receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,7062
Polymers27,1421
Non-polymers5641
Water54030
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)33.845, 55.365, 118.569
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Farnesoid X receptor / NR1H4 protein


Mass: 27142.119 Da / Num. of mol.: 1 / Fragment: Ligand-binding domain, residues 248-476
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H4 / Production host: Escherichia coli (E. coli) / References: UniProt: B7ZM06, UniProt: Q96RI1*PLUS
#2: Chemical ChemComp-635 / 1-methylethyl 8-fluoro-1,1-dimethyl-3-{[4-(3-morpholin-4-ylpropoxy)phenyl]carbonyl}-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate


Mass: 563.660 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H38FN3O5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 30 / 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: 2.05 Å3/Da / Density % sol: 39.89 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1mM Hepes, 27%PEG3350, 400mM MgCl2, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: May 14, 2008 / Details: mirrors
RadiationMonochromator: YALE MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. all: 17343 / Num. obs: 17343 / % possible obs: 93.9 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.3 % / Rmerge(I) obs: 0.038
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.435 / Mean I/σ(I) obs: 2.1 / Num. unique all: 1569 / % possible all: 87.9

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Processing

Software
NameVersionClassification
AMoREphasing
PHENIX(phenix.refine)refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in-house FXR ligand-binding domain structure

Resolution: 1.9→32.168 Å / SU ML: 0.33 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2705 882 5.09 %random
Rwork0.2458 ---
obs0.2471 17343 93.29 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 57.492 Å2 / ksol: 0.369 e/Å3
Refinement stepCycle: LAST / Resolution: 1.9→32.168 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1762 0 41 30 1833
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061846
X-RAY DIFFRACTIONf_angle_d0.9082499
X-RAY DIFFRACTIONf_dihedral_angle_d16.921690
X-RAY DIFFRACTIONf_chiral_restr0.058273
X-RAY DIFFRACTIONf_plane_restr0.004317
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-2.00780.38341260.32142433X-RAY DIFFRACTION85
2.0078-2.16280.31141470.27772687X-RAY DIFFRACTION93
2.1628-2.38030.34611450.26172741X-RAY DIFFRACTION94
2.3803-2.72460.32661590.26142748X-RAY DIFFRACTION95
2.7246-3.43210.26221620.25242783X-RAY DIFFRACTION94
3.4321-32.17230.22681430.22363069X-RAY DIFFRACTION98
Refinement TLS params.Method: refined / Origin x: -5.0697 Å / Origin y: -7.6295 Å / Origin z: 14.7957 Å
111213212223313233
T0.1655 Å2-0.0177 Å2-0.0074 Å2-0.2682 Å2-0.0135 Å2--0.2721 Å2
L0.546 °20.2935 °2-0.0116 °2-1.8917 °2-0.202 °2--3.3808 °2
S0.0376 Å °-0.0311 Å °-0.0561 Å °0.0105 Å °-0.0032 Å °0.1316 Å °0.0261 Å °-0.282 Å °-0.0001 Å °
Refinement TLS groupSelection details: chain A

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