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- PDB-3ue8: Kynurenine Aminotransferase II Inhibitors -

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Basic information

Entry
Database: PDB / ID: 3ue8
TitleKynurenine Aminotransferase II Inhibitors
ComponentsKynurenine/alpha-aminoadipate aminotransferase, mitochondrial
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / KAT II / kynurenine aminotransferase / 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 activity / kynurenine-glyoxylate transaminase / 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 activity / kynurenine-glyoxylate transaminase / 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 / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-09M / Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3.22 Å
AuthorsDounay, A.B. / Anderson, M. / Bechle, B.M. / Campbell, B.M. / Claffey, M.M. / Evdokimov, A. / Edelweiss, E. / Fonseca, K.R. / Gan, X. / Ghosh, S. ...Dounay, A.B. / Anderson, M. / Bechle, B.M. / Campbell, B.M. / Claffey, M.M. / Evdokimov, A. / Edelweiss, E. / Fonseca, K.R. / Gan, X. / Ghosh, S. / Hayward, M.M. / Horner, W. / Kim, J.Y. / McAllister, L.A. / Pandit, J. / Paradis, V. / Parikh, V.D. / Reese, M.R. / Rong, S.B. / Salafia, M.A. / Schuyten, K. / Strick, C.A. / Tuttle, J.B. / Valentine, J. / Wang, H. / Zawadzke, L.E. / Verhoest, P.R.
CitationJournal: ACS Med Chem Lett / Year: 2012
Title: Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia.
Authors: Dounay, A.B. / Anderson, M. / Bechle, B.M. / Campbell, B.M. / Claffey, M.M. / Evdokimov, A. / Evrard, E. / Fonseca, K.R. / Gan, X. / Ghosh, S. / Hayward, M.M. / Horner, W. / Kim, J.Y. / ...Authors: Dounay, A.B. / Anderson, M. / Bechle, B.M. / Campbell, B.M. / Claffey, M.M. / Evdokimov, A. / Evrard, E. / Fonseca, K.R. / Gan, X. / Ghosh, S. / Hayward, M.M. / Horner, W. / Kim, J.Y. / McAllister, L.A. / Pandit, J. / Paradis, V. / Parikh, V.D. / Reese, M.R. / Rong, S. / Salafia, M.A. / Schuyten, K. / Strick, C.A. / Tuttle, J.B. / Valentine, J. / Wang, H. / Zawadzke, L.E. / Verhoest, P.R.
History
DepositionOct 28, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 1, 2012Provider: repository / Type: Initial release
Revision 1.1Apr 18, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)99,0506
Polymers98,1652
Non-polymers8864
Water0
1
A: Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,5253
Polymers49,0821
Non-polymers4432
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,5253
Polymers49,0821
Non-polymers4432
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7810 Å2
ΔGint-65 kcal/mol
Surface area29220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.616, 116.597, 129.267
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 49082.301 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AADAT, KAT2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q8N5Z0, 2-aminoadipate transaminase, kynurenine-oxoglutarate transaminase
#2: Chemical ChemComp-09M / (5-hydroxy-4-{[(1-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)amino]methyl}-6-methylpyridin-3-yl)methyl dihydrogen phosphate


Mass: 407.314 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H18N3O7P
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl

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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: 2.44 Å3/Da / Density % sol: 49.63 %

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54 Å
RadiationMonochromator: Rigaku Varimax Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 3.2→100 Å / Num. all: 16200 / Num. obs: 16095 / % possible obs: 99.4 % / Biso Wilson estimate: 52.49 Å2

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Processing

Software
NameVersionClassification
StructureStudiodata collection
AMoREphasing
BUSTER2.11.2refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.22→30.43 Å / Cor.coef. Fo:Fc: 0.8996 / Cor.coef. Fo:Fc free: 0.8327 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2748 790 5 %RANDOM
Rwork0.2 ---
obs0.2038 15793 97.77 %-
all-16200 --
Displacement parametersBiso mean: 56.59 Å2
Baniso -1Baniso -2Baniso -3
1-21.7339 Å20 Å20 Å2
2---10.4546 Å20 Å2
3----11.2793 Å2
Refine analyzeLuzzati coordinate error obs: 0.547 Å
Refinement stepCycle: LAST / Resolution: 3.22→30.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6427 0 58 0 6485
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.016647HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.339038HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2249SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes161HARMONIC2
X-RAY DIFFRACTIONt_gen_planes995HARMONIC5
X-RAY DIFFRACTIONt_it6647HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.89
X-RAY DIFFRACTIONt_other_torsion24.39
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion864SEMIHARMONIC5
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_contact8129SEMIHARMONIC4
LS refinement shellResolution: 3.2→3.31 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.325 147 5.22 %
Rwork0.209 2667 -
all0.2149 2814 -
obs-1605 97.77 %
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)
10.31550.5742-0.16381.6944-0.52951.4523-0.07710.19150.2113-0.21910.25670.1984-0.1126-0.3456-0.17960.17450.0346-0.0372-0.20770.0672-0.117318.941521.120631.6026
21.44430.2264-0.441.9876-1.13493.0648-0.008-0.2715-0.0690.138-0.0486-0.05650.27730.17650.05660.06510.08530.0105-0.2070.0161-0.332618.32042.926557.8121
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A1 - 427
2X-RAY DIFFRACTION2{ B|* }B1 - 425

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