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- PDB-4cxw: Crystal structure of human FTO in complex with subfamily-selectiv... -

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Basic information

Entry
Database: PDB / ID: 4cxw
TitleCrystal structure of human FTO in complex with subfamily-selective inhibitor 12
ComponentsALPHA-KETOGLUTARATE-DEPENDENT DIOXYGENASE FTO
KeywordsOXIDOREDUCTASE / SMALL MOLECULAR PROBE
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-6MK / NICKEL (II) ION / Alpha-ketoglutarate-dependent dioxygenase FTO
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsToh, D.W. / Sun, L. / Tan, J. / Chen, Y. / Lau, L.Z.M. / Hong, W. / Woon, E.C.Y. / Gao, Y.G.
CitationJournal: Chem Sci / Year: 2015
Title: A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor ofN6-methyladenosine demethylase FTO.
Authors: Toh, J.D.W. / Sun, L. / Lau, L.Z.M. / Tan, J. / Low, J.J.A. / Tang, C.W.Q. / Cheong, E.J.Y. / Tan, M.J.H. / Chen, Y. / Hong, W. / Gao, Y.G. / Woon, E.C.Y.
History
DepositionApr 9, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 1, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 8, 2014Group: Non-polymer description
Revision 1.2Jan 21, 2015Group: Database references
Revision 1.3Apr 18, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.page_last ..._citation.journal_abbrev / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ALPHA-KETOGLUTARATE-DEPENDENT DIOXYGENASE FTO
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,2073
Polymers56,8231
Non-polymers3842
Water1,17165
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)141.613, 141.613, 83.812
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 / FAT MASS AND OBESITY-ASSOCIATED PROTEIN


Mass: 56823.047 Da / Num. of mol.: 1 / Fragment: DEMETHYLASE, RESIDUES 32-505
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21
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-NI / NICKEL (II) ION / Nickel


Mass: 58.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ni
#3: Chemical ChemComp-6MK / (2E)-4-[N'-(4-benzyl-pyridine-3-carbonyl)-hydrazino]-4-oxo-but-2-enoic acid / SHF-3


Mass: 325.319 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15N3O4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 65 / Source method: isolated from a natural source / Formula: H2O

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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: 2.85 Å3/Da / Density % sol: 56.84 % / Description: NONE
Crystal growDetails: 100 MM SODIUM CITRATE, PH5.6, 10% PEG 3350, 10% T-BUTANOL, 1 MM NISO4, 1.5 MM LIGAND

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 22, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.05→50 Å / Num. obs: 22939 / % possible obs: 95.2 % / Observed criterion σ(I): 1.98 / Redundancy: 2.57 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 11.28
Reflection shellResolution: 3.05→3.1 Å / Redundancy: 2.65 % / Rmerge(I) obs: 0.5 / Mean I/σ(I) obs: 1.98 / % possible all: 90.5

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE: 1.8.4_1496)refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4IE5

4ie5


Resolution: 3.1→40.88 Å / SU ML: 0.46 / σ(F): 1.3 / Phase error: 27.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2453 1096 5 %
Rwork0.1809 --
obs0.1841 21902 96.46 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.1→40.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3506 0 25 65 3596
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0123623
X-RAY DIFFRACTIONf_angle_d1.4384905
X-RAY DIFFRACTIONf_dihedral_angle_d17.1441354
X-RAY DIFFRACTIONf_chiral_restr0.052526
X-RAY DIFFRACTIONf_plane_restr0.007636
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1-3.24110.37531380.3432622X-RAY DIFFRACTION99
3.2411-3.41190.30991400.24992668X-RAY DIFFRACTION99
3.4119-3.62550.30031340.22452628X-RAY DIFFRACTION97
3.6255-3.90520.24421380.20562584X-RAY DIFFRACTION96
3.9052-4.29780.28721400.17542585X-RAY DIFFRACTION94
4.2978-4.91880.23321310.16032502X-RAY DIFFRACTION94
4.9188-6.19380.2391420.16892668X-RAY DIFFRACTION98
6.1938-40.88370.18391330.14622549X-RAY DIFFRACTION95

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