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- PDB-6aej: Crystal structure of human FTO in complex with small-molecule inh... -

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Basic information

Entry
Database: PDB / ID: 6aej
TitleCrystal structure of human FTO in complex with small-molecule inhibitors
ComponentsAlpha-ketoglutarate-dependent dioxygenase FTO,Alpha-ketoglutarate-dependent dioxygenase FTO
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR COMPLEX
Function / homology
Function and homology information


regulation of white fat cell proliferation / tRNA demethylase activity / Reversal of alkylation damage by DNA dioxygenases / mRNA N6-methyladenine demethylase / mRNA N6-methyladenosine dioxygenase activity / regulation of respiratory system process / regulation of lipid storage / : / regulation of brown fat cell differentiation / : ...regulation of white fat cell proliferation / tRNA demethylase activity / Reversal of alkylation damage by DNA dioxygenases / mRNA N6-methyladenine demethylase / mRNA N6-methyladenosine dioxygenase activity / regulation of respiratory system process / regulation of lipid storage / : / regulation of brown fat cell differentiation / : / : / oxidative RNA demethylase activity / broad specificity oxidative DNA demethylase activity / RNA repair / Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one donor, and incorporation of one atom of oxygen into each donor / DNA alkylation repair / oxidative demethylation / DNA demethylation / temperature homeostasis / mRNA destabilization / regulation of multicellular organism growth / adipose tissue development / ferrous iron binding / transferase activity / nuclear speck / intracellular membrane-bounded organelle / nucleoplasm / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
FTO C-terminal domain / Alpha-ketoglutarate-dependent dioxygenase FTO, C-terminal / Alpha-ketoglutarate-dependent dioxygenase FTO, catalytic domain / Alpha-ketoglutarate-dependent dioxygenase FTO / FTO, C-terminal domain superfamily / FTO catalytic domain / FTO C-terminal domain / FTO catalytic domain / Alpha-ketoglutarate-dependent dioxygenase AlkB-like / Alpha-ketoglutarate-dependent dioxygenase AlkB-like superfamily ...FTO C-terminal domain / Alpha-ketoglutarate-dependent dioxygenase FTO, C-terminal / Alpha-ketoglutarate-dependent dioxygenase FTO, catalytic domain / Alpha-ketoglutarate-dependent dioxygenase FTO / FTO, C-terminal domain superfamily / FTO catalytic domain / FTO C-terminal domain / FTO catalytic domain / Alpha-ketoglutarate-dependent dioxygenase AlkB-like / Alpha-ketoglutarate-dependent dioxygenase AlkB-like superfamily / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / Jelly Rolls / Up-down Bundle / Sandwich / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-7YC / Alpha-ketoglutarate-dependent dioxygenase FTO
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsWang, Y. / Cao, R. / Peng, S. / Zhang, W. / Huang, N.
CitationJournal: Sci Transl Med / Year: 2019
Title: Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1.
Authors: Peng, S. / Xiao, W. / Ju, D. / Sun, B. / Hou, N. / Liu, Q. / Wang, Y. / Zhao, H. / Gao, C. / Zhang, S. / Cao, R. / Li, P. / Huang, H. / Ma, Y. / Wang, Y. / Lai, W. / Ma, Z. / Zhang, W. / ...Authors: Peng, S. / Xiao, W. / Ju, D. / Sun, B. / Hou, N. / Liu, Q. / Wang, Y. / Zhao, H. / Gao, C. / Zhang, S. / Cao, R. / Li, P. / Huang, H. / Ma, Y. / Wang, Y. / Lai, W. / Ma, Z. / Zhang, W. / Huang, S. / Wang, H. / Zhang, Z. / Zhao, L. / Cai, T. / Zhao, Y.L. / Wang, F. / Nie, Y. / Zhi, G. / Yang, Y.G. / Zhang, E.E. / Huang, N.
History
DepositionAug 5, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 19, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Alpha-ketoglutarate-dependent dioxygenase FTO,Alpha-ketoglutarate-dependent dioxygenase FTO
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,5073
Polymers54,1221
Non-polymers3852
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area100 Å2
ΔGint-39 kcal/mol
Surface area20000 Å2
Unit cell
Length a, b, c (Å)142.057, 142.057, 84.672
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

#1: Protein Alpha-ketoglutarate-dependent dioxygenase FTO,Alpha-ketoglutarate-dependent dioxygenase FTO


Mass: 54121.973 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FTO, KIAA1752 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9C0B1, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one donor, and incorporation of one atom of oxygen into each donor
#2: Chemical ChemComp-7YC / (E)-3-[3-nitro-4,5-bis(oxidanyl)phenyl]-2-(1,3-oxazinan-3-ylcarbonyl)prop-2-enenitrile


Mass: 319.270 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H13N3O6
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn

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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: 3.04 Å3/Da / Density % sol: 59.51 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 10% (w/v) PEG 3350, 0.1M tri-sodium Citrate dehydrate pH5.6, 5.0mM 3-meT, 3.0mM NOG, VAPOR DIFFUSION, HANGING DROP, temperature 298.0K

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9797 Å
DetectorType: RIGAKU RAXIS II / Detector: IMAGE PLATE / Date: Jul 1, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9797 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. obs: 15756 / % possible obs: 99.9 % / Redundancy: 5.5 % / Net I/σ(I): 24
Reflection shellResolution: 2.8→2.85 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0123refinement
iMOSFLMdata reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3LFM

3lfm


Resolution: 2.8→50 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.95 / SU B: 0.006 / SU ML: 0 / Cross valid method: THROUGHOUT / ESU R: 0.302 / ESU R Free: 0.282 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2217 796 5.1 %RANDOM
Rwork0.2073 ---
obs0.22096 14959 99.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 81.625 Å2
Baniso -1Baniso -2Baniso -3
1--1.06 Å2-0.53 Å20 Å2
2---1.06 Å20 Å2
3---3.45 Å2
Refinement stepCycle: 1 / Resolution: 2.8→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3397 0 24 0 3421
LS refinement shellResolution: 2.794→2.867 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.265 46 -
Rwork0.308 1088 -
obs--98.1 %

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