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- PDB-4qho: Crystal structure of the human fat mass and obesity associated pr... -

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Basic information

Entry
Database: PDB / ID: 4qho
TitleCrystal structure of the human fat mass and obesity associated protein (FTO) in complex with CCO10
ComponentsAlpha-ketoglutarate-dependent dioxygenase FTO
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / jelly-roll motif / oxidoreductase / dioxygenase / double-stranded beta helix fold / nucleic acid demethylase / 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 / broad specificity oxidative DNA demethylase activity / oxidative RNA demethylase activity ...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 / broad specificity oxidative DNA demethylase activity / oxidative RNA demethylase activity / snRNA processing / 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 / RNA repair / DNA alkylation repair / 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 / 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-NKG / Alpha-ketoglutarate-dependent dioxygenase FTO
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.37 Å
AuthorsAik, W.S. / Clunie-O'Connor, C. / McDonough, M.A. / Schofield, C.J.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Structure-Based Design of Selective Fat Mass and Obesity Associated Protein (FTO) Inhibitors.
Authors: Shishodia, S. / Demetriades, M. / Zhang, D. / Tam, N.Y. / Maheswaran, P. / Clunie-O'Connor, C. / Tumber, A. / Leung, I.K.H. / Ng, Y.M. / Leissing, T.M. / El-Sagheer, A.H. / Salah, E. / ...Authors: Shishodia, S. / Demetriades, M. / Zhang, D. / Tam, N.Y. / Maheswaran, P. / Clunie-O'Connor, C. / Tumber, A. / Leung, I.K.H. / Ng, Y.M. / Leissing, T.M. / El-Sagheer, A.H. / Salah, E. / Brown, T. / Aik, W.S. / McDonough, M.A. / Schofield, C.J.
History
DepositionMay 28, 2014Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 3, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Database references / Derived calculations / Structure summary
Category: citation / citation_author ...citation / citation_author / database_2 / pdbx_struct_conn_angle / struct / struct_conn / struct_ref_seq_dif / struct_site
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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.title / _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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.2Feb 2, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.3Nov 8, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)57,2113
Polymers56,8231
Non-polymers3882
Water50428
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)141.384, 141.384, 83.954
Angle α, β, γ (deg.)90.000, 90.000, 120.000
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: UNP residues 32-505
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FTO, KIAA1752 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
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-NKG / N-{[3-hydroxy-6-(naphthalen-1-yl)pyridin-2-yl]carbonyl}glycine


Mass: 322.315 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H14N2O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / 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: 2.84 Å3/Da / Density % sol: 56.72 % / Mosaicity: 0.497 ° / Mosaicity esd: 0.004 °
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 100mM trisodium citrate, 8% PEG 3350, 4% tert-butanol, 8mg/ml protein, 1mM ZnSO4, 1mM inhibitor, pH 5.6, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 1.2716 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Sep 25, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.2716 Å / Relative weight: 1
ReflectionResolution: 2.32→50 Å / Num. all: 26710 / Num. obs: 26707 / % possible obs: 100 % / Observed criterion σ(F): -3 / Redundancy: 7.2 % / Biso Wilson estimate: 67.42 Å2 / Rmerge(I) obs: 0.204 / Χ2: 1.226 / Net I/σ(I): 11.5
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. unique allΧ2% possible allRmerge(I) obs
2.32-2.44.31226970.921100
2.4-2.55.411.726480.986100
2.5-2.616.610.626841.0021000.953
2.61-2.757.111.326671.1481000.66
2.75-2.927.810.626711.2181000.426
2.92-3.157.78.726551.3431000.291
3.15-3.478.16.426691.3681000.228
3.47-3.978.24.326851.3461000.202
3.97-58.4326541.37299.90.193
5-508.6226771.2411000.192

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACT3.14data extraction
GDAdata collection
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ID 4IE5

4ie5


Resolution: 2.37→49.48 Å / Isotropic thermal model: isotropic
RfactorNum. reflection% reflectionSelection details
Rfree0.2076 1872 7.45 %random
Rwork0.1769 ---
all-26707 --
obs-25134 94.1 %-
Displacement parametersBiso max: 195.14 Å2 / Biso mean: 86.97 Å2 / Biso min: 55.24 Å2
Refinement stepCycle: LAST / Resolution: 2.37→49.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3408 0 25 28 3461
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONf_bond_d0.011
X-RAY DIFFRACTIONf_angle_deg1.216
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkRefine-IDNum. reflection obs% reflection obs (%)
2.3787-2.44310.32591410.2731X-RAY DIFFRACTION1919100
5.5888-40.820.1751360.1536X-RAY DIFFRACTION193499.8
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.60540.88570.79233.07390.98312.85380.1773-0.10020.0560.4565-0.182-0.56570.20550.2084-0.03910.74220.0447-0.05660.7763-0.01460.851235.5107-6.1798-19.6657
23.6285-0.09020.90292.07180.74353.31250.4614-0.6475-0.4010.3451-0.2611-0.23720.5143-0.354-0.09340.7555-0.1165-0.04330.71430.03230.695523.2909-13.827-17.0833
33.62991.23351.15423.6797-0.44172.76710.35640.0186-0.08430.0111-0.2454-0.16450.27430.321-0.06880.51940.024-0.0320.5853-0.08690.602232.9021-3.7104-22.677
44.19520.85821.18772.7957-0.09873.72360.17220.3636-0.4827-0.1086-0.0801-0.14420.25910.058-0.09130.6548-0.03830.02460.6184-0.10290.61454.3142-19.5632-40.4047
53.430.83050.55092.1815-0.39361.06610.25660.6909-0.573-0.6080.0015-0.3220.36680.5269-0.20861.0561-0.00040.04511.1679-0.27860.848512.2613-21.5367-50.1674
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resseq 28:91 )A28 - 91
2X-RAY DIFFRACTION2chain 'A' and (resseq 92:162 )A92 - 162
3X-RAY DIFFRACTION3chain 'A' and (resseq 163:330 )A163 - 330
4X-RAY DIFFRACTION4chain 'A' and (resseq 331:457 )A331 - 457
5X-RAY DIFFRACTION5chain 'A' and (resseq 458:504 )A458 - 504

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