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- PDB-8hul: X-ray structure of human PPAR delta ligand binding domain-lanifib... -

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Basic information

Entry
Database: PDB / ID: 8hul
TitleX-ray structure of human PPAR delta ligand binding domain-lanifibranor co-crystals obtained by co-crystallization
ComponentsPeroxisome proliferator-activated receptor delta
KeywordsTRANSCRIPTION / Nuclear receptor / Protein-ligand complex / PPAR
Function / homology
Function and homology information


keratinocyte migration / linoleic acid binding / positive regulation of skeletal muscle tissue regeneration / fat cell proliferation / positive regulation of epidermis development / axon ensheathment / positive regulation of fat cell proliferation / regulation of skeletal muscle satellite cell proliferation / D-glucose transmembrane transport / negative regulation of smooth muscle cell migration ...keratinocyte migration / linoleic acid binding / positive regulation of skeletal muscle tissue regeneration / fat cell proliferation / positive regulation of epidermis development / axon ensheathment / positive regulation of fat cell proliferation / regulation of skeletal muscle satellite cell proliferation / D-glucose transmembrane transport / negative regulation of smooth muscle cell migration / proteoglycan metabolic process / fatty acid catabolic process / negative regulation of collagen biosynthetic process / positive regulation of myoblast proliferation / positive regulation of fatty acid oxidation / phospholipid biosynthetic process / Carnitine shuttle / negative regulation of myoblast differentiation / response to vitamin A / Signaling by Retinoic Acid / positive regulation of fatty acid metabolic process / fatty acid beta-oxidation / cell-substrate adhesion / negative regulation of cholesterol storage / decidualization / nuclear steroid receptor activity / keratinocyte proliferation / NF-kappaB binding / adipose tissue development / positive regulation of fat cell differentiation / positive regulation of insulin secretion involved in cellular response to glucose stimulus / response to glucose / fatty acid transport / cellular response to nutrient levels / cholesterol metabolic process / energy homeostasis / intracellular receptor signaling pathway / hormone-mediated signaling pathway / embryo implantation / negative regulation of miRNA transcription / response to activity / generation of precursor metabolites and energy / apoptotic signaling pathway / negative regulation of smooth muscle cell proliferation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / wound healing / fatty acid metabolic process / negative regulation of cell growth / Nuclear Receptor transcription pathway / lipid metabolic process / negative regulation of inflammatory response / DNA-binding transcription repressor activity, RNA polymerase II-specific / transcription coactivator binding / vasodilation / glucose metabolic process / nuclear receptor activity / negative regulation of epithelial cell proliferation / sequence-specific double-stranded DNA binding / heart development / cellular response to lipopolysaccharide / cellular response to hypoxia / DNA-binding transcription factor activity, RNA polymerase II-specific / cell differentiation / cell population proliferation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of DNA-templated transcription / apoptotic process / lipid binding / positive regulation of gene expression / 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 / DNA binding / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
Peroxisome proliferator-activated receptor, beta / Peroxisome proliferator-activated 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 ...Peroxisome proliferator-activated receptor, beta / Peroxisome proliferator-activated 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
Similarity search - Domain/homology
Chem-BJB / Peroxisome proliferator-activated receptor delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.461 Å
AuthorsKamata, S. / Honda, A. / Machida, Y. / Uchii, K. / Shiiyama, Y. / Masuda, R. / Oyama, T. / Ishii, I.
Funding support Japan, 3items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)22K15049 Japan
Japan Society for the Promotion of Science (JSPS)22H05577 Japan
Japan Agency for Medical Research and Development (AMED)JP21am0101071 Japan
CitationJournal: Antioxidants / Year: 2023
Title: Functional and Structural Insights into the Human PPAR alpha / delta / gamma Targeting Preferences of Anti-NASH Investigational Drugs, Lanifibranor, Seladelpar, and Elafibranor.
Authors: Kamata, S. / Honda, A. / Ishikawa, R. / Akahane, M. / Fujita, A. / Kaneko, C. / Miyawaki, S. / Habu, Y. / Shiiyama, Y. / Uchii, K. / Machida, Y. / Oyama, T. / Ishii, I.
History
DepositionDec 24, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 9, 2023Provider: repository / Type: Initial release
Revision 1.1Sep 6, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.page_first / _citation.pdbx_database_id_PubMed ..._citation.page_first / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Peroxisome proliferator-activated receptor delta
B: Peroxisome proliferator-activated receptor delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,9254
Polymers63,0552
Non-polymers8702
Water00
1
A: Peroxisome proliferator-activated receptor delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9632
Polymers31,5281
Non-polymers4351
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Peroxisome proliferator-activated receptor delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9632
Polymers31,5281
Non-polymers4351
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.166, 94.948, 96.932
Angle α, β, γ (deg.)90.000, 97.780, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Peroxisome proliferator-activated receptor delta / PPAR-delta / NUCI / Nuclear hormone receptor 1 / NUC1 / Nuclear receptor subfamily 1 group C member ...PPAR-delta / NUCI / Nuclear hormone receptor 1 / NUC1 / Nuclear receptor subfamily 1 group C member 2 / Peroxisome proliferator-activated receptor beta / PPAR-beta


Mass: 31527.648 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARD, NR1C2, PPARB / Plasmid: pet28a / Production host: Escherichia coli (E. coli) / References: UniProt: Q03181
#2: Chemical ChemComp-BJB / 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloro-indol-2-yl]butanoic acid


Mass: 434.916 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H15ClN2O4S2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: 2.83 Å3/Da / Density % sol: 56.57 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.05 M Bis-tris propane (pH 8.0), 14% PEG8000, 0.1 M KSCN, 6% propanediol, 0.001 M EDTA, 0.001 M CaCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-17A / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 25, 2022 / Details: Mirrors
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.46→48.02 Å / Num. obs: 25193 / % possible obs: 98.9 % / Redundancy: 3.5 % / Biso Wilson estimate: 36.26 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.042 / Rrim(I) all: 0.079 / Net I/σ(I): 12.3 / Num. measured all: 87903
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.46-2.563.50.353.727910.9160.2170.41297.9
8.87-48.023.40.0285470.9980.0180.03396.2

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation6.5 Å48.02 Å
Translation6.5 Å48.02 Å

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.5.21data scaling
PHASER2.7.16phasing
PHENIX1.11.1-2575-000refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7WGL

7wgl


Resolution: 2.461→38.805 Å / SU ML: 0.33 / Cross valid method: FREE R-VALUE / σ(F): 1.93 / Phase error: 28.26 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2433 2163 4.77 %
Rwork0.2109 43204 -
obs0.2126 25149 90.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 103.24 Å2 / Biso mean: 41.6428 Å2 / Biso min: 14.93 Å2
Refinement stepCycle: final / Resolution: 2.461→38.805 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4146 0 84 0 4230
Biso mean--51.42 --
Num. residues----514
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024306
X-RAY DIFFRACTIONf_angle_d0.4475826
X-RAY DIFFRACTIONf_chiral_restr0.034657
X-RAY DIFFRACTIONf_plane_restr0.002728
X-RAY DIFFRACTIONf_dihedral_angle_d15.6092590
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.4614-2.51860.38651310.2952271487
2.5186-2.58160.37961330.2703287989
2.5816-2.65140.30671200.2634282189
2.6514-2.72940.31321240.2541285489
2.7294-2.81750.26851460.2396284889
2.8175-2.91810.29441380.2489277789
2.9181-3.03490.25841520.2474286288
3.0349-3.1730.26591320.2421280789
3.173-3.34020.26571550.2204290891
3.3402-3.54930.2791340.2222298792
3.5493-3.82310.25021510.1996290392
3.8231-4.20750.1951540.1817291492
4.2075-4.81530.22621700.1777295893
4.8153-6.06310.2151310.2049298893
6.0631-38.8050.18591920.1671298495

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