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- PDB-9h66: Steroidal Selective Modulators of FXR with Therapeutic Potential -

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Basic information

Entry
Database: PDB / ID: 9h66
TitleSteroidal Selective Modulators of FXR with Therapeutic Potential
Components
  • Bile acid receptor
  • Nuclear receptor coactivator 2
KeywordsNUCLEAR PROTEIN / nuclear receptor / ligand binding domain / complex
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 / intracellular triglyceride homeostasis / cellular response to bile acid / negative regulation of very-low-density lipoprotein particle remodeling / negative regulation of interleukin-1 production ...: / chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic 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 / positive regulation of insulin receptor signaling pathway / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / 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 / Notch signaling pathway / : / positive regulation of adipose tissue development / Regulation of lipid metabolism by PPARalpha / negative regulation of canonical NF-kappaB signal transduction / peroxisome proliferator activated receptor signaling pathway / regulation of cellular response to insulin stimulus / 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 / circadian regulation of gene expression / mRNA transcription by RNA polymerase II / Heme signaling / euchromatin / Transcriptional activation of mitochondrial biogenesis / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / PPARA activates gene expression / Cytoprotection by HMOX1 / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / negative regulation of inflammatory response / RNA polymerase II transcription regulator complex / nuclear receptor activity / : / HATs acetylate histones / cellular response to lipopolysaccharide / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / 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: 2.6 Å
AuthorsKydd-Sinclair, D. / Watson, K.A.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Mol.Biol. / Year: 2025
Title: Structural Basis of Novel Bile Acid-Based Modulators of FXR.
Authors: Kydd-Sinclair, D. / Packer, G.L. / Weymouth-Wilson, A.C. / Watson, K.A.
History
DepositionOct 23, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 10, 2025Provider: repository / Type: Initial release
Revision 1.1Sep 17, 2025Group: Database references / Category: citation / Item: _citation.journal_volume

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bile acid receptor
B: Bile acid receptor
C: Bile acid receptor
D: Bile acid receptor
E: Nuclear receptor coactivator 2
F: Nuclear receptor coactivator 2
G: Nuclear receptor coactivator 2
H: Nuclear receptor coactivator 2
I: Nuclear receptor coactivator 2
J: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,61114
Polymers117,96410
Non-polymers2,6474
Water1,31573
1
A: Bile acid receptor
B: Bile acid receptor
E: Nuclear receptor coactivator 2
F: Nuclear receptor coactivator 2
G: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,3057
Polymers58,9825
Non-polymers1,3242
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4850 Å2
ΔGint-30 kcal/mol
Surface area22060 Å2
MethodPISA
2
C: Bile acid receptor
D: Bile acid receptor
H: Nuclear receptor coactivator 2
I: Nuclear receptor coactivator 2
J: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,3057
Polymers58,9825
Non-polymers1,3242
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4380 Å2
ΔGint-32 kcal/mol
Surface area21870 Å2
MethodPISA
3
D: Bile acid receptor
J: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,3563
Polymers28,6942
Non-polymers6621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-8 kcal/mol
Surface area11590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.580, 101.214, 104.809
Angle α, β, γ (deg.)90.000, 90.106, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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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: 27100.191 Da / Num. of mol.: 4 / Mutation: E277A, E350A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H4, BAR, FXR, HRR1, RIP14 / Production host: Escherichia coli BL21(DE3) (bacteria) / 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: 1593.844 Da / Num. of mol.: 6 / Source method: obtained synthetically / Details: Steroid receptor coactivator 2 peptide 3 (SRC2-3) / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical
ChemComp-R3U / (4~{R})-4-[(3~{R},4~{R},5~{S},6~{R},7~{R},8~{S},9~{S},10~{R},13~{R},14~{R},17~{R})-6-ethyl-4-fluoranyl-10,13-dimethyl-3,7-bis(oxidanyl)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1~{H}-cyclopenta[a]phenanthren-17-yl]-~{N}-[4-(trifluoromethyloxy)phenyl]sulfonyl-pentanamide


Mass: 661.788 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C33H47F4NO6S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 73 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 3.13 Å3/Da / Density % sol: 60.68 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 4.2
Details: 0.1M sodium phosphate dibasic, 0.2M lithium sulphate pH4.2, 20% PEG2000 MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jul 10, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.6→57.92 Å / Num. obs: 44957 / % possible obs: 99.96 % / Redundancy: 6.4 % / Biso Wilson estimate: 66.65 Å2 / CC1/2: 0.902 / CC star: 0.974 / Rmerge(I) obs: 0.137 / Rrim(I) all: 0.1498 / Net I/σ(I): 8.83
Reflection shellResolution: 2.6→2.693 Å / Rmerge(I) obs: 2.978 / Num. unique obs: 4461 / CC1/2: 0.519

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
xia2data reduction
xia2data scaling
Cootmodel building
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4QE6

4qe6
PDB Unreleased entry


Resolution: 2.6→57.92 Å / SU ML: 0.6189 / Cross valid method: FREE R-VALUE / σ(F): 1.91 / Phase error: 41.1554
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.312 2222 4.94 %
Rwork0.2592 42735 -
obs0.262 44957 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 81.19 Å2
Refinement stepCycle: LAST / Resolution: 2.6→57.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7747 0 180 73 8000
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00958147
X-RAY DIFFRACTIONf_angle_d1.23711104
X-RAY DIFFRACTIONf_chiral_restr0.07591298
X-RAY DIFFRACTIONf_plane_restr0.00951399
X-RAY DIFFRACTIONf_dihedral_angle_d10.10841188
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.650.4171380.3642623X-RAY DIFFRACTION98.54
2.65-2.710.42211330.3892656X-RAY DIFFRACTION99.86
2.71-2.780.39491200.37582696X-RAY DIFFRACTION100
2.78-2.860.43411530.38312642X-RAY DIFFRACTION99.96
2.86-2.940.39091410.35012631X-RAY DIFFRACTION100
2.94-3.040.36391470.32972670X-RAY DIFFRACTION100
3.04-3.150.3761240.31922698X-RAY DIFFRACTION100
3.15-3.270.39711530.30292605X-RAY DIFFRACTION100
3.27-3.420.36681420.27582680X-RAY DIFFRACTION99.96
3.42-3.60.38351300.29362684X-RAY DIFFRACTION99.96
3.6-3.830.34681280.26982683X-RAY DIFFRACTION99.96
3.83-4.120.31421480.25862666X-RAY DIFFRACTION99.96
4.12-4.540.26351320.20732675X-RAY DIFFRACTION99.93
4.54-5.190.25951360.19962695X-RAY DIFFRACTION100
5.19-6.540.30031320.25942697X-RAY DIFFRACTION100
6.54-57.920.26731650.22032734X-RAY DIFFRACTION99.93

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