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- PDB-9lq3: Crystal structure of Linafexor-FXR complex -

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Basic information

Entry
Database: PDB / ID: 9lq3
TitleCrystal structure of Linafexor-FXR complex
Components
  • Bile acid receptor
  • Nuclear receptor coactivator 2
KeywordsNUCLEAR PROTEIN / Bile acid receptor / nonbile acid agonist / Linafexor
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 / bile acid binding / cell-cell junction assembly / cellular response to fatty acid / regulation of cholesterol metabolic process / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / negative regulation of interleukin-2 production / bile acid and bile salt transport / intracellular glucose homeostasis / locomotor rhythm / positive regulation of interleukin-17 production / aryl hydrocarbon receptor binding / negative regulation of interleukin-6 production / negative regulation of type II interferon production / cellular response to Thyroglobulin triiodothyronine / regulation of lipid metabolic process / regulation of glucose metabolic process / 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 / positive regulation of insulin receptor signaling pathway / fatty acid homeostasis / positive regulation of insulin secretion involved in cellular response to glucose stimulus / nuclear retinoid X receptor binding / cellular response to hormone stimulus / Recycling of bile acids and salts / transcription regulator inhibitor activity / intracellular receptor signaling pathway / positive regulation of adipose tissue development / : / Notch signaling pathway / Regulation of lipid metabolism by PPARalpha / peroxisome proliferator activated receptor signaling pathway / regulation of cellular response to insulin stimulus / negative regulation of canonical NF-kappaB signal transduction / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / response to progesterone / cholesterol homeostasis / nuclear receptor binding / transcription coregulator binding / negative regulation of smoothened signaling pathway / RNA polymerase II transcription regulatory region sequence-specific DNA binding / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / circadian regulation of gene expression / Heme signaling / PPARA activates gene expression / euchromatin / Transcriptional activation of mitochondrial biogenesis / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Cytoprotection by HMOX1 / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / negative regulation of inflammatory response / RNA polymerase II transcription regulator complex / nuclear receptor activity / : / HATs acetylate histones / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / cellular response to lipopolysaccharide / DNA-binding transcription activator activity, RNA polymerase II-specific / transcription regulator complex / Estrogen-dependent gene expression / sequence-specific DNA binding / transcription by RNA polymerase II / DNA-binding transcription factor activity, RNA polymerase II-specific / cell differentiation / transcription coactivator activity / receptor complex / transcription cis-regulatory region binding / protein dimerization activity / defense response to bacterium / nuclear speck / nuclear body / RNA polymerase II cis-regulatory region sequence-specific DNA binding / inflammatory response / DNA-binding transcription factor activity / protein domain specific binding / innate immune response
Similarity search - Function
Bile acid receptor, ligand binding domain / Thyroid hormone receptor / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / 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 ...Bile acid receptor, ligand binding domain / Thyroid hormone receptor / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / 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 / 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
Similarity search - Domain/homology
: / Nuclear receptor coactivator 2 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsYao, B. / Li, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: To Be Published
Title: Crystal structure of Linafexor-FXR complex
Authors: Yao, B. / Li, Y.
History
DepositionJan 27, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 6, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bile acid receptor
C: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,4303
Polymers27,8582
Non-polymers5711
Water25214
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area960 Å2
ΔGint-9 kcal/mol
Surface area11680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.478, 67.455, 58.304
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-612-

HOH

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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: 26494.521 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H4, BAR, FXR, HRR1, RIP14 / Production host: Escherichia coli (E. coli) / References: UniProt: Q96RI1
#2: Protein/peptide Nuclear receptor coactivator 2 / NCoA-2 / Class E basic helix-loop-helix protein 75 / bHLHe75 / Transcriptional intermediary factor 2 / hTIF2


Mass: 1363.608 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NCOA2, BHLHE75, SRC2, TIF2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15596
#3: Chemical ChemComp-A1ELK / 3-[4-[(1~{S},5~{R})-3-[[3-[2,6-bis(chloranyl)phenyl]-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-8-azabicyclo[3.2.1]octan-8-yl]-2-fluoranyl-phenyl]-4~{H}-1,2,4-oxadiazol-5-one / Linafexor


Mass: 571.427 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H25Cl2FN4O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.27 Å3/Da / Density % sol: 45.8 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: 0.2 M Sodium malonate pH 7.0, 20% Polyethylene glycol 3,350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Dec 21, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.64→50 Å / Num. obs: 7697 / % possible obs: 98.7 % / Redundancy: 11.7 % / CC1/2: 1 / CC star: 1 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.021 / Rrim(I) all: 0.071 / Χ2: 0.921 / Net I/σ(I): 8.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
2.64-2.698.90.9253530.7460.9240.3140.9811.00993.6
2.69-2.739.60.7173620.9180.9780.2340.7560.92895.8
2.73-2.799.70.6463520.870.9650.2120.6820.99592.6
2.79-2.8410.40.6353560.9120.9770.2010.6681.03896.7
2.84-2.9111.80.5663940.9790.9950.1710.5920.99899.7
2.91-2.9712.50.5463850.9440.9850.160.570.943100
2.97-3.0513.10.4493770.9790.9950.1280.4670.918100
3.05-3.1312.70.3153740.9810.9950.0920.3280.929100
3.13-3.2212.60.2733940.9770.9940.080.2850.927100
3.22-3.3312.40.223880.9870.9970.0650.230.949100
3.33-3.4411.60.173770.9940.9990.0520.1780.95498.7
3.44-3.5812.40.1323810.9960.9990.0390.1380.94599.7
3.58-3.7412.90.1113910.9940.9990.0330.1160.939100
3.74-3.9412.90.0923820.990.9970.0280.0970.965100
3.94-4.1912.50.0763950.9970.9990.0230.080.81100
4.19-4.5111.60.073980.9930.9980.0230.0740.78599.3
4.51-4.9612.50.0653880.9960.9990.020.0680.725100
4.96-5.6812.50.064000.9970.9990.0180.0630.94699.8
5.68-7.1411.20.0544080.9970.9990.0170.0560.89598.8
7.14-3010.60.0444420.99910.0140.0470.91398.9

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
REFMAC1.19.2refinement
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→46.23 Å / SU ML: 0.48 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 34.89 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2929 643 9.87 %
Rwork0.2673 --
obs0.2699 6513 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.8→46.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1868 0 39 14 1921
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0031949
X-RAY DIFFRACTIONf_angle_d0.612644
X-RAY DIFFRACTIONf_dihedral_angle_d19.741739
X-RAY DIFFRACTIONf_chiral_restr0.036305
X-RAY DIFFRACTIONf_plane_restr0.003331
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-3.020.43091290.40741123X-RAY DIFFRACTION100
3.02-3.320.3981260.33521174X-RAY DIFFRACTION100
3.32-3.80.33081230.30311147X-RAY DIFFRACTION100
3.8-4.790.25041300.24191182X-RAY DIFFRACTION100
4.79-46.230.26681350.2391244X-RAY DIFFRACTION99

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