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

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Basic information

Entry
Database: PDB / ID: 7tfp
TitleHuman Ornithine Aminotransferase cocrystallized with its inhibitor, (1S,3S)-3-amino-4-(difluoromethylene)cyclopentane-1-carboxylic acid.
ComponentsOrnithine aminotransferase, mitochondrial
KeywordsTRANSFERASE / Human Ornithine Aminotransferase / hOAT / OAT / mechanism-based inhibitor / MBI / irreversible inhibitor / inactivator
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-I2V / PYRIDOXAL-5'-PHOSPHATE / Ornithine aminotransferase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.71 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 6, 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)135,4847
Polymers134,5813
Non-polymers9034
Water4,540252
1
A: Ornithine aminotransferase, mitochondrial
hetero molecules

A: Ornithine aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,2154
Polymers89,7212
Non-polymers4942
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_554-x,-x+y,-z-1/31
Buried area11410 Å2
ΔGint-61 kcal/mol
Surface area26170 Å2
MethodPISA
2
B: Ornithine aminotransferase, mitochondrial
hetero molecules

C: Ornithine aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,3765
Polymers89,7212
Non-polymers6553
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_444-y-1,x-y-1,z-1/31
Buried area11430 Å2
ΔGint-64 kcal/mol
Surface area25690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.170, 115.170, 186.810
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221
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-614-

HOH

21A-690-

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-PLP / PYRIDOXAL-5'-PHOSPHATE / VITAMIN B6 Phosphate / Pyridoxal phosphate


Mass: 247.142 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H10NO6P
#3: Chemical ChemComp-I2V / (1S,3S,4S)-3-amino-4-(fluoromethyl)cyclopentane-1-carboxylic acid


Mass: 161.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H12FNO2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 252 / 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: 2.66 Å3/Da / Density % sol: 53.72 %
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: Jul 3, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.127 Å / Relative weight: 1
ReflectionResolution: 2.71→57.58 Å / Num. obs: 37903 / % possible obs: 96.5 % / Redundancy: 6.4 % / Biso Wilson estimate: 53.9 Å2 / CC1/2: 0.986 / Net I/σ(I): 6
Reflection shellResolution: 2.71→2.78 Å / Num. unique obs: 2823 / CC1/2: 0.31

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1OAT

1oat


Resolution: 2.71→43.99 Å / SU ML: 0.377 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.059
Stereochemistry target values: GEOSTD + MONOMER LIBRARY + CDL V1.2
RfactorNum. reflection% reflection
Rfree0.268 1976 5.22 %
Rwork0.227 --
obs0.229 37851 95.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 54.95 Å2
Refinement stepCycle: LAST / Resolution: 2.71→43.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9468 0 30 252 9750
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0029719
X-RAY DIFFRACTIONf_angle_d0.48513209
X-RAY DIFFRACTIONf_dihedral_angle_d13.2893575
X-RAY DIFFRACTIONf_chiral_restr0.0431462
X-RAY DIFFRACTIONf_plane_restr0.0041696
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.71-2.780.36221600.33322562X-RAY DIFFRACTION98
2.78-2.850.36881390.33362604X-RAY DIFFRACTION98
2.85-2.940.35641420.32772582X-RAY DIFFRACTION98
2.94-3.030.41591400.31512584X-RAY DIFFRACTION97
3.03-3.140.34491200.29722449X-RAY DIFFRACTION92
3.14-3.270.31791490.272452X-RAY DIFFRACTION94
3.27-3.410.27911120.27262623X-RAY DIFFRACTION97
3.41-3.590.31841520.24882592X-RAY DIFFRACTION97
3.59-3.820.26911630.21852548X-RAY DIFFRACTION97
3.82-4.110.22341470.1992613X-RAY DIFFRACTION97
4.11-4.530.23971190.18952588X-RAY DIFFRACTION96
4.53-5.180.21631420.17672599X-RAY DIFFRACTION95
5.18-6.520.22971370.20822435X-RAY DIFFRACTION90
6.53-43.990.21791540.17992644X-RAY DIFFRACTION92

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