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- PDB-7ted: Human Ornithine Aminotransferase cocrystallized with its inhibito... -

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Basic information

Entry
Database: PDB / ID: 7ted
TitleHuman Ornithine Aminotransferase cocrystallized with its inhibitor, (S,E)-3-amino-4-(fluoromethylene)cyclopent-1-ene-1-carboxylate
ComponentsOrnithine aminotransferase, mitochondrial
KeywordsTRANSFERASE/Inhibitor / Human Ornithine Aminotransferase / hOAT / OAT / mechanism-based inhibitor / MBI / irreversible inhibitor / inactivator / TRANSFERASE / TRANSFERASE-Inhibitor complex
Function / homology
Function and homology information


arginine catabolic process to proline via ornithine / ornithine aminotransferase activity / ornithine aminotransferase / arginine catabolic process to glutamate / L-proline biosynthetic process / Glutamate and glutamine metabolism / visual perception / pyridoxal phosphate binding / mitochondrial matrix / mitochondrion ...arginine catabolic process to proline via ornithine / ornithine aminotransferase activity / ornithine aminotransferase / arginine catabolic process to glutamate / L-proline biosynthetic process / Glutamate and glutamine metabolism / visual perception / pyridoxal phosphate binding / mitochondrial matrix / mitochondrion / nucleoplasm / identical protein binding / cytoplasm
Similarity search - Function
Ornithine aminotransferase / : / Aminotransferases class-III pyridoxal-phosphate attachment site. / Aminotransferase class-III / Aminotransferase class-III / Pyridoxal phosphate-dependent transferase, small domain / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase
Similarity search - Domain/homology
Chem-I1T / PYRIDOXAL-5'-PHOSPHATE / Ornithine aminotransferase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.63 Å
AuthorsButrin, A. / Zhu, W. / Silverman, R. / Liu, D.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)1R01CA260250-01 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01DA030604 United States
CitationJournal: J.Am.Chem.Soc. / Year: 2022
Title: Rational Design, Synthesis, and Mechanism of (3 S ,4 R )-3-Amino-4-(difluoromethyl)cyclopent-1-ene-1-carboxylic Acid: Employing a Second-Deprotonation Strategy for Selectivity of Human ...Title: Rational Design, Synthesis, and Mechanism of (3 S ,4 R )-3-Amino-4-(difluoromethyl)cyclopent-1-ene-1-carboxylic Acid: Employing a Second-Deprotonation Strategy for Selectivity of Human Ornithine Aminotransferase over GABA Aminotransferase.
Authors: Zhu, W. / Butrin, A. / Melani, R.D. / Doubleday, P.F. / Ferreira, G.M. / Tavares, M.T. / Habeeb Mohammad, T.S. / Beaupre, B.A. / Kelleher, N.L. / Moran, G.R. / Liu, D. / Silverman, R.B.
History
DepositionJan 4, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 6, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 13, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 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

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Assembly

Deposited unit
A: Ornithine aminotransferase, mitochondrial
B: Ornithine aminotransferase, mitochondrial
C: Ornithine aminotransferase, mitochondrial
D: Ornithine aminotransferase, mitochondrial
E: Ornithine aminotransferase, mitochondrial
F: Ornithine aminotransferase, mitochondrial
G: Ornithine aminotransferase, mitochondrial
H: Ornithine aminotransferase, mitochondrial
I: Ornithine aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)407,09718
Polymers403,7439
Non-polymers3,3549
Water6,035335
1
A: Ornithine aminotransferase, mitochondrial
B: Ornithine aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,4974
Polymers89,7212
Non-polymers7772
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10650 Å2
ΔGint-64 kcal/mol
Surface area25890 Å2
MethodPISA
2
C: Ornithine aminotransferase, mitochondrial
I: Ornithine aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,3564
Polymers89,7212
Non-polymers6352
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11240 Å2
ΔGint-64 kcal/mol
Surface area26040 Å2
MethodPISA
3
D: Ornithine aminotransferase, mitochondrial
hetero molecules

E: Ornithine aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,4974
Polymers89,7212
Non-polymers7772
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_446-x-1/2,y-1/2,-z+11
Buried area10590 Å2
ΔGint-68 kcal/mol
Surface area26110 Å2
MethodPISA
4
F: Ornithine aminotransferase, mitochondrial
hetero molecules

F: Ornithine aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,4974
Polymers89,7212
Non-polymers7772
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area10630 Å2
ΔGint-63 kcal/mol
Surface area26150 Å2
MethodPISA
5
G: Ornithine aminotransferase, mitochondrial
hetero molecules

H: Ornithine aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,4974
Polymers89,7212
Non-polymers7772
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_455-x-1/2,y+1/2,-z1
Buried area10760 Å2
ΔGint-64 kcal/mol
Surface area26430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)200.110, 115.430, 185.760
Angle α, β, γ (deg.)90.000, 94.850, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11F-609-

HOH

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Components

#1: Protein
Ornithine aminotransferase, mitochondrial / / Ornithine delta-aminotransferase / Ornithine--oxo-acid aminotransferase


Mass: 44860.320 Da / Num. of mol.: 9
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: OAT / Production host: Escherichia coli (E. coli) / References: UniProt: P04181, ornithine aminotransferase
#2: Chemical
ChemComp-I1T / (1S,3R,4S)-3-formyl-4-[({3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]pyridin-4-yl}methyl)amino]cyclopentane-1-carboxylic acid


Mass: 388.310 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C15H21N2O8P / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PLP / PYRIDOXAL-5'-PHOSPHATE / VITAMIN B6 Phosphate / Pyridoxal phosphate


Mass: 247.142 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H10NO6P / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 335 / 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: 2.65 Å3/Da / Density % sol: 53.54 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: After purification, OAT was buffer exchanged into the crystallization buffer (50 mM Tricine pH 7.8) supplied supplemented with 1 mM 2-ketoglutarate. The protein was concentrated to 6.5 mg/mL. ...Details: After purification, OAT was buffer exchanged into the crystallization buffer (50 mM Tricine pH 7.8) supplied supplemented with 1 mM 2-ketoglutarate. The protein was concentrated to 6.5 mg/mL. Previously reported crystallization conditions were optimized using the hanging drop vapor diffusion method by varying PEG 6000 (8-12%), NaCl (100-250 mM), and glycerol (0%-10%) with 100 mM Tricine pH 7.8 was being kept constant as the buffer. For each hanging drop, 2 uL of protein solution was mixed with an equal volume of well solution and 0.5 uL of ligand. The crystals with the best morphology and size grew in a final condition containing 12% PEG 6000, 200 mM NaCl, 10% glycerol, and 100 mM Tricine pH 7.8. Crystals were transferred to a cryo-protectant solution (well solution supplemented with 30% glycerol) and flash-frozen in liquid nitrogen

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.127 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Dec 13, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.127 Å / Relative weight: 1
ReflectionResolution: 2.63→43.73 Å / Num. obs: 123624 / % possible obs: 98.9 % / Redundancy: 4.7 % / Biso Wilson estimate: 46.48 Å2 / CC1/2: 0.987 / Net I/σ(I): 8.2
Reflection shellResolution: 2.63→2.7 Å / Mean I/σ(I) obs: 1.7 / Num. unique obs: 9062 / CC1/2: 0.294

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1OAT

1oat


Resolution: 2.63→43.4 Å / SU ML: 0.4167 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 29.5568
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2876 6092 4.93 %
Rwork0.2812 117514 -
obs0.2815 123606 98.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 18.93 Å2
Refinement stepCycle: LAST / Resolution: 2.63→43.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms28449 0 224 335 29008
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01129347
X-RAY DIFFRACTIONf_angle_d1.549839890
X-RAY DIFFRACTIONf_chiral_restr0.09534392
X-RAY DIFFRACTIONf_plane_restr0.00615129
X-RAY DIFFRACTIONf_dihedral_angle_d15.043710846
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.63-2.660.35582150.34363815X-RAY DIFFRACTION98.51
2.66-2.690.34281780.34153945X-RAY DIFFRACTION98.52
2.69-2.720.3722060.343848X-RAY DIFFRACTION98.42
2.72-2.760.3221890.34513934X-RAY DIFFRACTION98.66
2.76-2.790.3441710.34143885X-RAY DIFFRACTION98.69
2.79-2.830.3511960.33583886X-RAY DIFFRACTION98.27
2.83-2.870.33992080.33273848X-RAY DIFFRACTION96.55
2.87-2.920.30331820.33743722X-RAY DIFFRACTION95.24
2.92-2.960.34642170.32053928X-RAY DIFFRACTION98.29
2.96-3.010.32912030.31923872X-RAY DIFFRACTION99.76
3.01-3.060.34022060.31213958X-RAY DIFFRACTION99.78
3.06-3.120.29171800.30814008X-RAY DIFFRACTION99.71
3.12-3.180.31242040.30443927X-RAY DIFFRACTION99.81
3.18-3.240.31932140.30863895X-RAY DIFFRACTION99.68
3.24-3.310.32011950.3024008X-RAY DIFFRACTION99.69
3.31-3.390.3322030.30993958X-RAY DIFFRACTION99.76
3.39-3.480.31271940.29613935X-RAY DIFFRACTION99.78
3.48-3.570.29422270.28073917X-RAY DIFFRACTION99.57
3.57-3.670.27072130.27573915X-RAY DIFFRACTION99.66
3.67-3.790.25962010.27713942X-RAY DIFFRACTION99.64
3.79-3.930.24552070.27823966X-RAY DIFFRACTION99.69
3.93-4.090.29031940.27343950X-RAY DIFFRACTION99.42
4.09-4.270.25772120.26553966X-RAY DIFFRACTION99.19
4.27-4.50.2692080.26323885X-RAY DIFFRACTION98.86
4.5-4.780.26822420.25723912X-RAY DIFFRACTION98.51
4.78-5.150.27141860.26023859X-RAY DIFFRACTION97.21
5.15-5.660.2741880.25823783X-RAY DIFFRACTION94.68
5.66-6.480.26312570.27213955X-RAY DIFFRACTION99.76
6.48-8.150.27072380.2383987X-RAY DIFFRACTION99.93
8.16-43.40.24441580.2294105X-RAY DIFFRACTION98.79

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