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- PDB-4ge7: Kynurenine Aminotransferase II Inhibitors -

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Basic information

Entry
Database: PDB / ID: 4ge7
TitleKynurenine Aminotransferase II Inhibitors
ComponentsKynurenine/alpha-aminoadipate aminotransferase, mitochondrial
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Aminotransferase / irreversible inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


glycine transaminase / methionine-glyoxylate transaminase / glycine:2-oxoglutarate aminotransferase activity / methionine-glyoxylate transaminase activity / 2-aminoadipate transaminase / alpha-amino acid metabolic process / 2-aminoadipate transaminase activity / kynurenine-glyoxylate transaminase / kynurenine-glyoxylate transaminase activity / L-lysine catabolic process to acetyl-CoA via saccharopine ...glycine transaminase / methionine-glyoxylate transaminase / glycine:2-oxoglutarate aminotransferase activity / methionine-glyoxylate transaminase activity / 2-aminoadipate transaminase / alpha-amino acid metabolic process / 2-aminoadipate transaminase activity / kynurenine-glyoxylate transaminase / kynurenine-glyoxylate transaminase activity / L-lysine catabolic process to acetyl-CoA via saccharopine / kynurenine-oxoglutarate transaminase / kynurenine-oxoglutarate transaminase activity / kynurenine metabolic process / Lysine catabolism / glutamate metabolic process / 2-oxoglutarate metabolic process / Tryptophan catabolism / biosynthetic process / pyridoxal phosphate binding / mitochondrial matrix / protein homodimerization activity
Similarity search - Function
: / Aminotransferase, class I/classII / Aminotransferase class I and II / Aspartate Aminotransferase, domain 1 / Aspartate Aminotransferase, domain 1 / Aspartate Aminotransferase; domain 2 / Type I PLP-dependent aspartate aminotransferase-like (Major domain) / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase / Alpha-Beta Complex ...: / Aminotransferase, class I/classII / Aminotransferase class I and II / Aspartate Aminotransferase, domain 1 / Aspartate Aminotransferase, domain 1 / Aspartate Aminotransferase; domain 2 / Type I PLP-dependent aspartate aminotransferase-like (Major domain) / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase / Alpha-Beta Complex / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-0K5 / Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsPandit, J.
CitationJournal: ACS Med Chem Lett / Year: 2013
Title: Structure-Based Design of Irreversible Human KAT II Inhibitors: Discovery of New Potency-Enhancing Interactions.
Authors: Tuttle, J.B. / Anderson, M. / Bechle, B.M. / Campbell, B.M. / Chang, C. / Dounay, A.B. / Evrard, E. / Fonseca, K.R. / Gan, X. / Ghosh, S. / Horner, W. / James, L.C. / Kim, J.Y. / McAllister, ...Authors: Tuttle, J.B. / Anderson, M. / Bechle, B.M. / Campbell, B.M. / Chang, C. / Dounay, A.B. / Evrard, E. / Fonseca, K.R. / Gan, X. / Ghosh, S. / Horner, W. / James, L.C. / Kim, J.Y. / McAllister, L.A. / Pandit, J. / Parikh, V.D. / Rago, B.J. / Salafia, M.A. / Strick, C.A. / Zawadzke, L.E. / Verhoest, P.R.
History
DepositionAug 1, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 7, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 16, 2014Group: Database references
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Dec 6, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
B: Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,9314
Polymers97,9322
Non-polymers9992
Water11,349630
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9380 Å2
ΔGint-68 kcal/mol
Surface area30910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.740, 114.968, 116.548
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial / KAT/AadAT / 2-aminoadipate aminotransferase / 2-aminoadipate transaminase / Alpha-aminoadipate ...KAT/AadAT / 2-aminoadipate aminotransferase / 2-aminoadipate transaminase / Alpha-aminoadipate aminotransferase / AadAT / Kynurenine aminotransferase II / Kynurenine--oxoglutarate aminotransferase II / Kynurenine--oxoglutarate transaminase 2 / Kynurenine--oxoglutarate transaminase II


Mass: 48966.078 Da / Num. of mol.: 2 / Mutation: K240S, F241G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AADAT, KAT2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8N5Z0, 2-aminoadipate transaminase, kynurenine-oxoglutarate transaminase
#2: Chemical ChemComp-0K5 / (5-hydroxy-4-{[(1-hydroxy-2-oxo-6-phenoxy-1,2-dihydroquinolin-3-yl)amino]methyl}-6-methylpyridin-3-yl)methyl dihydrogen phosphate


Mass: 499.410 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H22N3O8P
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 630 / 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: 2.93 Å3/Da / Density % sol: 58.06 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→44 Å / Num. obs: 60372 / % possible obs: 89.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 4.7 % / Biso Wilson estimate: 27.16 Å2 / Rmerge(I) obs: 0.084 / Χ2: 1.303 / Net I/σ(I): 9.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.1-2.144.10.45122731.5168.1
2.14-2.184.20.36924921.045174.8
2.18-2.224.30.3526921.069181.1
2.22-2.264.40.31629410.988187
2.26-2.314.50.29430130.985190.2
2.31-2.374.60.25730830.971192.2
2.37-2.424.70.22431211.012193.3
2.42-2.494.70.20731681193.8
2.49-2.564.80.19531460.988193.8
2.56-2.654.80.16531481.058193.8
2.65-2.744.90.16231481.146193.4
2.74-2.854.90.13631471.253193
2.85-2.984.90.10831431.224193.2
2.98-3.144.90.08731281.164192.5
3.14-3.3350.06731341.16192.2
3.33-3.5950.05731151.422191.5
3.59-3.9550.06531042.408191.2
3.95-4.5250.04431061.764190
4.52-5.750.03431061.38189.4
5.7-444.90.03231642.248186.6

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
BUSTER-TNTBUSTER 2.9.2refinement
PDB_EXTRACT3.11data extraction
JDirectordata collection
HKL-2000data reduction
PHASERphasing
BUSTER2.9.2refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3UE8

3ue8


Resolution: 2.1→33.51 Å / Cor.coef. Fo:Fc: 0.9409 / Cor.coef. Fo:Fc free: 0.9351 / Occupancy max: 1 / Occupancy min: 0.5 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2016 3075 5.1 %RANDOM
Rwork0.1782 ---
obs0.1794 60312 --
Displacement parametersBiso max: 151.44 Å2 / Biso mean: 35.593 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--7.4526 Å20 Å20 Å2
2--5.8341 Å20 Å2
3---1.6185 Å2
Refine analyzeLuzzati coordinate error obs: 0.239 Å
Refinement stepCycle: LAST / Resolution: 2.1→33.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6690 0 70 630 7390
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2350SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes164HARMONIC2
X-RAY DIFFRACTIONt_gen_planes982HARMONIC5
X-RAY DIFFRACTIONt_it6854HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion900SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8601SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6930HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg9418HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion3.07
X-RAY DIFFRACTIONt_other_torsion19.07
LS refinement shellResolution: 2.1→2.15 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2517 176 5.23 %
Rwork0.2067 3188 -
all0.209 3364 -
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)
10.64360.0880.04140.8502-0.27530.5743-0.00890.0668-0.0244-0.1141-0.0096-0.14720.06670.05080.0184-0.04530.00530.0075-0.0633-0.0095-0.05072.529914.1709-50.1311
20.32670.0594-0.10740.608-0.20820.5436-0.00560.0012-0.0643-0.0015-0.0052-0.03250.1349-0.04820.01070.0093-0.0032-0.0003-0.05160.0087-0.056-10.5364-7.382-33.4671
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|1 - A|428 A|999 - A|999 }A1 - 428
2X-RAY DIFFRACTION1{ A|1 - A|428 A|999 - A|999 }A501 - 999
3X-RAY DIFFRACTION2{ B|1 - B|428 B|999 - B|999 }B1 - 428
4X-RAY DIFFRACTION2{ B|1 - B|428 B|999 - B|999 }B501 - 999

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