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- PDB-7e8z: Crystal structure of the human fat mass and obesity associated pr... -

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Basic information

Entry
Database: PDB / ID: 7e8z
TitleCrystal structure of the human fat mass and obesity associated protein (FTO) in complex with SS81
ComponentsAlpha-ketoglutarate-dependent dioxygenase FTO
KeywordsOXIDOREDUCTASE / Double-stranded beta helix / 2OG and Fe(II)-dependent oxygenase / RNA demethylase
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 / oxidative RNA demethylase activity / broad specificity oxidative DNA 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 / oxidative RNA demethylase activity / broad specificity oxidative DNA 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 / plasma membrane / cytosol / cytoplasm
Similarity search - Function
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 superfamily
Similarity search - Domain/homology
Chem-HZX / Alpha-ketoglutarate-dependent dioxygenase FTO
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsTam, N.Y. / Ng, Y.M. / Shishodia, S. / McDonough, M.A. / Schofield, C.J. / Aik, W.S.
Funding support Hong Kong, 1items
OrganizationGrant numberCountry
The University Grants Committee, Research Grants Council (RGC)22301719 Hong Kong
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
DepositionMar 3, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 13, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 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 1.2Nov 29, 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)57,2213
Polymers56,8231
Non-polymers3982
Water21612
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area100 Å2
ΔGint-39 kcal/mol
Surface area19880 Å2
Unit cell
Length a, b, c (Å)142.293, 142.293, 83.901
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 / U6 small nuclear RNA (2'-O-methyladenosine-N(6)-)- ...Fat mass and obesity-associated protein / U6 small nuclear RNA (2'-O-methyladenosine-N(6)-)-demethylase FTO / U6 small nuclear RNA N(6)-methyladenosine-demethylase FTO / mRNA (2'-O-methyladenosine-N(6)-)-demethylase FTO / m6A(m)-demethylase FTO / mRNA N(6)-methyladenosine demethylase FTO / tRNA N1-methyl adenine demethylase FTO


Mass: 56823.047 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 ...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, mRNA N6-methyladenine demethylase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-HZX / 2-[[6-[(4-nitrophenyl)amino]-3-oxidanyl-pyridin-2-yl]carbonylamino]ethanoic acid


Mass: 332.268 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H12N4O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Formula: H2O
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: 2.88 Å3/Da / Density % sol: 57.24 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 13.5% PEG3350, 100 mM trisodium citrate pH 5.6, 4% tert-butanol, 1 mM NADH

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9999 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Dec 24, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.55→71.14 Å / Num. obs: 20599 / % possible obs: 99.84 % / Redundancy: 3.18 % / Biso Wilson estimate: 61.9 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.087 / Rpim(I) all: 0.06 / Rrim(I) all: 0.106 / Net I/σ(I): 10.4
Reflection shellResolution: 2.55→2.59 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.766 / Mean I/σ(I) obs: 0.5 / Num. unique obs: 1000 / CC1/2: 0.57 / Rpim(I) all: 0.514 / Rrim(I) all: 0.927 / % possible all: 99.8

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Processing

Software
NameVersionClassification
DIALSdata scaling
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
DIALSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4IE5

4ie5


Resolution: 2.55→41.08 Å / SU ML: 0.41 / Cross valid method: THROUGHOUT / σ(F): 1.96 / Phase error: 28.44 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.237 937 4.59 %
Rwork0.1954 19491 -
obs0.1971 20428 98.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 181.14 Å2 / Biso mean: 84.8688 Å2 / Biso min: 40.87 Å2
Refinement stepCycle: final / Resolution: 2.55→41.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3420 0 25 12 3457
Biso mean--75.06 66.59 -
Num. residues----441
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.55-2.680.33151570.3312621277895
2.68-2.850.34051030.26892793289699
2.85-3.070.29771680.26332782295099
3.07-3.380.29231740.254227782952100
3.38-3.870.22421200.199728222942100
3.87-4.870.216840.163828792963100
4.87-41.080.18841310.163428162947100
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)
16.070.92292.76434.06310.46163.82010.15020.6819-0.8023-0.25930.13130.22930.3110.1698-0.34470.5168-0.0562-0.00450.453-0.07550.6604-12.977-33.8872-35.89
25.69880.55443.90897.67270.34324.3220.04251.199-0.5429-0.31320.2853-0.75770.14610.8843-0.16180.4393-0.0382-0.03880.7129-0.13950.69164.758-27.781-31.7359
35.66982.25531.63512.33580.75911.68930.2357-0.0453-0.30980.218-0.0503-0.14880.19070.1811-0.17140.48320.0084-0.01820.46020.07420.4691.8403-22.3468-23.8812
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 27 through 91 )A27 - 91
2X-RAY DIFFRACTION2chain 'A' and (resid 92 through 129 )A92 - 129
3X-RAY DIFFRACTION3chain 'A' and (resid 130 through 503 )A130 - 503

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