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- PDB-6ak4: Crystal structure of human FTO in complex with small-molecule inh... -

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Basic information

Entry
Database: PDB / ID: 6ak4
TitleCrystal structure of human FTO in complex with small-molecule inhibitors
ComponentsAlpha-ketoglutarate-dependent dioxygenase FTO,Alpha-ketoglutarate-dependent dioxygenase FTO
KeywordsOXIDOREDUCTASE / 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-PD9 / 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 30, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 10, 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)54,4933
Polymers54,1221
Non-polymers3712
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area19270 Å2
Unit cell
Length a, b, c (Å)141.770, 141.770, 83.751
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 / Mutation: deletions, insertion
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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-PD9 / (~{E})-2-cyano-~{N},~{N}-diethyl-3-[3-nitro-4,5-bis(oxidanyl)phenyl]prop-2-enamide / Entacapone


Mass: 305.286 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H15N3O5 / Comment: medication, inhibitor*YM

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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: 2.99 Å3/Da / Density % sol: 58.9 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 10.0% (W/V) PEG 3350, 100 MM SODIUM CITRATE, PH 5.6, 7% TERT-BUTANOL, 1 MM ZNSO4, 1 MM COMPOUND, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 298K
PH range: 5.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Sep 26, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.8→70.89 Å / Num. obs: 14979 / % possible obs: 97.3 % / Redundancy: 5.4 % / Net I/σ(I): 14.4
Reflection shellResolution: 2.8→2.96 Å

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Processing

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

3lfm


Resolution: 2.8→70.88 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.916 / SU B: 13.127 / SU ML: 0.263 / Cross valid method: THROUGHOUT / ESU R: 1.306 / ESU R Free: 0.354 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.253 748 5 %RANDOM
Rwork0.209 ---
obs0.211 14231 97.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 86.09 Å2
Baniso -1Baniso -2Baniso -3
1--0.37 Å2-0.19 Å20 Å2
2---0.37 Å20 Å2
3---1.21 Å2
Refinement stepCycle: LAST / Resolution: 2.8→70.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3341 0 23 0 3364
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0193467
X-RAY DIFFRACTIONr_bond_other_d0.0020.023158
X-RAY DIFFRACTIONr_angle_refined_deg1.1251.9474727
X-RAY DIFFRACTIONr_angle_other_deg0.9083.0017246
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8455429
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.88724.207164
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.96215547
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.2941520
X-RAY DIFFRACTIONr_chiral_restr0.0620.2516
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213967
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02820
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.9638.81702
X-RAY DIFFRACTIONr_mcbond_other2.9618.7991701
X-RAY DIFFRACTIONr_mcangle_it4.83513.192123
X-RAY DIFFRACTIONr_mcangle_other4.83413.1922124
X-RAY DIFFRACTIONr_scbond_it2.7168.9751765
X-RAY DIFFRACTIONr_scbond_other2.7158.9761766
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.57313.3822601
X-RAY DIFFRACTIONr_long_range_B_refined7.58269.8823767
X-RAY DIFFRACTIONr_long_range_B_other7.58169.8943768
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.8→2.88 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.352 47 -
Rwork0.234 929 -
obs--85.76 %

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