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- PDB-4ge9: Kynurenine Aminotransferase II Inhibitors -

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Basic information

Entry
Database: PDB / ID: 4ge9
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 / 2-aminoadipate transaminase activity / kynurenine-glyoxylate transaminase activity / kynurenine-glyoxylate transaminase / alpha-amino acid metabolic process / 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 / 2-aminoadipate transaminase activity / kynurenine-glyoxylate transaminase activity / kynurenine-glyoxylate transaminase / alpha-amino acid metabolic process / 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-0L0 / Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.43 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 1.2Feb 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
C: Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
D: Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)197,9108
Polymers195,8004
Non-polymers2,1104
Water13,421745
1
A: Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
B: Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,9554
Polymers97,9002
Non-polymers1,0552
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9240 Å2
ΔGint-65 kcal/mol
Surface area30220 Å2
MethodPISA
2
C: Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
D: Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,9554
Polymers97,9002
Non-polymers1,0552
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9310 Å2
ΔGint-65 kcal/mol
Surface area30260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.155, 107.050, 116.599
Angle α, β, γ (deg.)90.000, 94.520, 90.000
Int Tables number4
Space group name H-MP1211

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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.: 4 / 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-0L0 / (4-{[(6-benzyl-1-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)amino]methyl}-5-hydroxy-6-methylpyridin-3-yl)methyl dihydrogen phosphate


Mass: 527.463 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H26N3O8P
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 745 / 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: 2.2 Å3/Da / Density % sol: 44.02 %

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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: 2.425→116.237 Å / Num. all: 63063 / Num. obs: 63063 / % possible obs: 98.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.6 % / Biso Wilson estimate: 37.02 Å2 / Rsym value: 0.114 / Net I/σ(I): 8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.42-2.563.50.4891.43172191760.48997.7
2.56-2.713.60.3951.83086186410.39598.1
2.71-2.93.60.292.42937281330.2997.9
2.9-3.133.60.2163.12774076660.21698.7
3.13-3.433.60.1384.92571570670.13899.2
3.43-3.833.60.0946.92305063590.09498.4
3.83-4.433.60.0777.91998855290.07797.1
4.43-5.423.60.0649.41687747040.06497.1
5.42-7.673.60.06110.41356237250.06198.9
7.67-116.2373.50.03913.6717220630.03998.1

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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 / Resolution: 2.43→35.58 Å / Cor.coef. Fo:Fc: 0.9353 / Cor.coef. Fo:Fc free: 0.8998 / Occupancy max: 1 / Occupancy min: 1 / SU R Cruickshank DPI: 0.686 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2295 3193 5.1 %RANDOM
Rwork0.1754 ---
obs0.1781 62628 98.08 %-
Displacement parametersBiso max: 182.83 Å2 / Biso mean: 52.3552 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-3.4729 Å20 Å24.7084 Å2
2--7.4868 Å20 Å2
3----10.9597 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: LAST / Resolution: 2.43→35.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13376 0 148 745 14269
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d4704SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes328HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1980HARMONIC5
X-RAY DIFFRACTIONt_it13864HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1804SEMIHARMONIC5
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_contact16500SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d13864HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg18844HARMONIC21.24
X-RAY DIFFRACTIONt_omega_torsion2.92
X-RAY DIFFRACTIONt_other_torsion21.33
LS refinement shellResolution: 2.43→2.49 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2573 229 4.98 %
Rwork0.1917 4365 -
all0.1951 4594 -
obs--98.08 %
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)
11.26970.7336-0.09233.0985-0.00350.11590.0739-0.1195-0.04840.4011-0.03640.23050.0303-0.0138-0.0374-0.2466-0.00870.0581-0.1528-0.00330.03759.0217-2.8054-49.656
21.12940.65980.20253.0217-0.02830.12620.0525-0.103-0.1090.403-0.0306-0.5141-0.01690.0186-0.0219-0.3151-0.00190.0483-0.1814-0.00290.254234.746913.3271-49.7295
30.69391.24820.27943.2203-0.27370.33290.1525-0.07450.22240.3186-0.17990.5711-0.02850.02120.02740.3260.0032-0.1268-0.304-0.0489-0.01524.5024-14.44158.4425
41.11541.26680.60253.8073-0.07130.72020.1731-0.0848-0.06040.286-0.1665-0.11870.01530.0379-0.00660.3241-0.0458-0.1023-0.2650.0085-0.324130.15521.87368.3538
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|1 - A|428 A|4000 - A|4000 }A1 - 428
2X-RAY DIFFRACTION1{ A|1 - A|428 A|4000 - A|4000 }A4000
3X-RAY DIFFRACTION2{ B|1 - B|428 B|4000 - B|4000 }B1 - 428
4X-RAY DIFFRACTION2{ B|1 - B|428 B|4000 - B|4000 }B4000
5X-RAY DIFFRACTION3{ C|1 - C|428 C|4000 - C|4000 }C1 - 428
6X-RAY DIFFRACTION3{ C|1 - C|428 C|4000 - C|4000 }C4000
7X-RAY DIFFRACTION4{ D|1 - D|428 D|4000 - D|4000 }D1 - 428
8X-RAY DIFFRACTION4{ D|1 - D|428 D|4000 - D|4000 }D4000

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