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- PDB-4ge4: Kynurenine Aminotransferase II Inhibitors -

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Basic information

Entry
Database: PDB / ID: 4ge4
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-0KE / Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.41 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_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)98,7754
Polymers97,9002
Non-polymers8752
Water4,774265
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8980 Å2
ΔGint-67 kcal/mol
Surface area30260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.944, 111.944, 137.508
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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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: 48950.074 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-0KE / (5-hydroxy-4-{[(1-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)amino]methyl}-6-methylpyridin-3-yl)methyl dihydrogen phosphate


Mass: 437.340 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H20N3O8P
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 265 / 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: 2.54 Å3/Da / Density % sol: 51.58 %

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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: 2.405→137.508 Å / Num. all: 39279 / Num. obs: 39279 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 10.9 % / Biso Wilson estimate: 55.38 Å2 / Rsym value: 0.069 / Net I/σ(I): 23.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.4-2.5411.20.4971.56312356570.497100
2.54-2.6911.10.3412.25958553470.341100
2.69-2.8711.20.2253.45643550600.225100
2.87-3.111.10.1455.35240647100.145100
3.1-3.4110.0888.44803243600.088100
3.4-3.810.80.0611.84252239380.06100
3.8-4.3910.60.04514.63705734930.045100
4.39-5.3810.50.0415.83165230070.04100
5.38-7.6110.30.04115.32417623470.041100
7.61-137.5089.40.03317.91276913600.03399.4

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
BUSTER-TNTBUSTER 2.9.3refinement
PDB_EXTRACT3.11data extraction
JDirectordata collection
XDSdata reduction
PHASERphasing
BUSTER2.9.3refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3UE8

3ue8


Resolution: 2.41→34.84 Å / Cor.coef. Fo:Fc: 0.9429 / Cor.coef. Fo:Fc free: 0.9272 / Occupancy max: 1 / Occupancy min: 1 / SU R Cruickshank DPI: 0.355 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2128 1959 5.02 %RANDOM
Rwork0.1868 ---
obs0.1881 38991 99.98 %-
all-39279 --
Displacement parametersBiso max: 156.24 Å2 / Biso mean: 52.2435 Å2 / Biso min: 24.35 Å2
Baniso -1Baniso -2Baniso -3
1-2.0821 Å20 Å20 Å2
2--2.0821 Å20 Å2
3----4.1642 Å2
Refine analyzeLuzzati coordinate error obs: 0.284 Å
Refinement stepCycle: LAST / Resolution: 2.41→34.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6640 0 60 265 6965
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2330SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes162HARMONIC2
X-RAY DIFFRACTIONt_gen_planes987HARMONIC5
X-RAY DIFFRACTIONt_it6865HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion896SEMIHARMONIC5
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_contact7958SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6865HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg9329HARMONIC21.18
X-RAY DIFFRACTIONt_omega_torsion3.19
X-RAY DIFFRACTIONt_other_torsion19.16
LS refinement shellResolution: 2.41→2.47 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.218 142 5 %
Rwork0.1841 2700 -
all0.1859 2842 -
obs--99.98 %
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)
10.84820.00530.20541.2528-0.07790.73070.01690.0198-0.07910.2044-0.0309-0.06330.07740.2640.014-0.13230.04350.0501-0.046-0.0025-0.100827.99212.3539-8.7359
20.6609-0.0391-0.15171.4403-0.18590.66740.02450.16160.0687-0.1836-0.0558-0.0938-0.11760.17170.0314-0.1302-0.03850.0341-0.04290.0371-0.108227.84325.0817-29.0779
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|1 - A|428 }A1 - 428
2X-RAY DIFFRACTION2{ B|1 - B|428 }B1 - 428

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