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

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Basic information

Entry
Database: PDB / ID: 7tev
TitleHuman Ornithine Aminotransferase cocrystallized with its inhibitor, (3S,4R)-3-amino-4-(difluoromethyl)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 / Ornithine aminotransferase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.91 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 5, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,7466
Polymers134,5813
Non-polymers1,1653
Water10,665592
1
A: Ornithine aminotransferase, mitochondrial
hetero molecules

A: 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_555y,x,-z1
Buried area10580 Å2
ΔGint-63 kcal/mol
Surface area25800 Å2
MethodPISA
2
B: Ornithine aminotransferase, mitochondrial
hetero molecules

C: 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_454-y-1,x-y,z-1/31
Buried area10400 Å2
ΔGint-62 kcal/mol
Surface area25820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.827, 115.827, 187.412
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z
Components on special symmetry positions
IDModelComponents
11A-631-

HOH

21A-775-

HOH

31C-628-

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.: 3
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.: 3 / Source method: obtained synthetically / Formula: C15H21N2O8P / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 592 / 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: 2.7 Å3/Da / Density % sol: 54.39 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: After purification, hOAT was buffer exchanged into the crystallization buffer (50 mM Tricine pH 7.8) supplemented with 1 mM 2-ketoglutarate. The protein was concentrated to 6.5 mg/mL. ...Details: After purification, hOAT was buffer exchanged into the crystallization buffer (50 mM Tricine pH 7.8) 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 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: Sep 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.127 Å / Relative weight: 1
ReflectionResolution: 1.907→88.438 Å / Num. obs: 113351 / % possible obs: 99.8 % / Redundancy: 12.7 % / Biso Wilson estimate: 34.48 Å2 / CC1/2: 0.998 / Net I/σ(I): 10.6
Reflection shellResolution: 1.907→1.94 Å / Num. unique obs: 5443 / CC1/2: 0.296

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Processing

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

1oat


Resolution: 1.91→44.22 Å / SU ML: 0.3071 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.1251
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.269 5651 5 %
Rwork0.2564 107283 -
obs0.2571 112934 99.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 23.34 Å2
Refinement stepCycle: LAST / Resolution: 1.91→44.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9464 0 78 592 10134
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01239766
X-RAY DIFFRACTIONf_angle_d1.567313272
X-RAY DIFFRACTIONf_chiral_restr0.12041463
X-RAY DIFFRACTIONf_plane_restr0.00731702
X-RAY DIFFRACTIONf_dihedral_angle_d13.77063611
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.91-1.930.35681520.37493072X-RAY DIFFRACTION86.13
1.93-1.950.35022100.34923544X-RAY DIFFRACTION99.97
1.95-1.980.32681780.34783531X-RAY DIFFRACTION100
1.98-20.34092070.34713558X-RAY DIFFRACTION100
2-2.030.3472070.3373538X-RAY DIFFRACTION100
2.03-2.050.36221810.33343556X-RAY DIFFRACTION99.97
2.05-2.080.36451740.33423566X-RAY DIFFRACTION100
2.08-2.120.34692010.32723549X-RAY DIFFRACTION100
2.12-2.150.32652220.32353548X-RAY DIFFRACTION100
2.15-2.180.331550.32693594X-RAY DIFFRACTION100
2.18-2.220.32351870.31593557X-RAY DIFFRACTION100
2.22-2.260.34711890.31643569X-RAY DIFFRACTION100
2.26-2.30.32181900.30363570X-RAY DIFFRACTION100
2.3-2.350.32351820.30983564X-RAY DIFFRACTION100
2.35-2.40.27631680.30123598X-RAY DIFFRACTION100
2.4-2.460.33531740.30043614X-RAY DIFFRACTION100
2.46-2.520.31531760.29383531X-RAY DIFFRACTION99.04
2.52-2.590.31561810.2943601X-RAY DIFFRACTION99.71
2.59-2.660.30421670.29513600X-RAY DIFFRACTION100
2.66-2.750.30551870.28783600X-RAY DIFFRACTION100
2.75-2.850.29041700.28253579X-RAY DIFFRACTION100
2.85-2.960.31491730.28763639X-RAY DIFFRACTION100
2.96-3.10.28582350.27993556X-RAY DIFFRACTION100
3.1-3.260.2812080.25833584X-RAY DIFFRACTION100
3.26-3.470.26311930.24653626X-RAY DIFFRACTION100
3.47-3.730.24731820.23643667X-RAY DIFFRACTION100
3.73-4.110.23791970.21983607X-RAY DIFFRACTION100
4.11-4.70.21962370.20863598X-RAY DIFFRACTION99.35
4.7-5.920.22041830.20453694X-RAY DIFFRACTION99.51
5.92-44.220.18651850.18123873X-RAY DIFFRACTION99.88

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