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- PDB-5tqh: IDH1 R132H mutant in complex with IDH889 -

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Basic information

Entry
Database: PDB / ID: 5tqh
TitleIDH1 R132H mutant in complex with IDH889
ComponentsIsocitrate dehydrogenase [NADP] cytoplasmic
KeywordsOXIDOREDUCTASE / Isocitrate dehydrogenase / Rossmann fold / NADPH / inhibitor
Function / homology
Function and homology information


Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate / NADPH regeneration / regulation of phospholipid catabolic process / regulation of phospholipid biosynthetic process / NFE2L2 regulating TCA cycle genes / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / isocitrate dehydrogenase (NADP+) activity / 2-oxoglutarate metabolic process / NADP metabolic process ...Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate / NADPH regeneration / regulation of phospholipid catabolic process / regulation of phospholipid biosynthetic process / NFE2L2 regulating TCA cycle genes / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / isocitrate dehydrogenase (NADP+) activity / 2-oxoglutarate metabolic process / NADP metabolic process / glyoxylate cycle / response to steroid hormone / female gonad development / peroxisomal matrix / glutathione metabolic process / tricarboxylic acid cycle / Peroxisomal protein import / peroxisome / NAD binding / tertiary granule lumen / NADP binding / secretory granule lumen / response to oxidative stress / ficolin-1-rich granule lumen / cadherin binding / Neutrophil degranulation / magnesium ion binding / protein homodimerization activity / mitochondrion / extracellular exosome / extracellular region / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Isocitrate dehydrogenase NADP-dependent / Isopropylmalate Dehydrogenase / Isopropylmalate Dehydrogenase / Isocitrate/isopropylmalate dehydrogenase, conserved site / Isocitrate and isopropylmalate dehydrogenases signature. / Isopropylmalate dehydrogenase-like domain / Isocitrate/isopropylmalate dehydrogenase / Isocitrate/isopropylmalate dehydrogenase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-7J2 / CITRATE ANION / Chem-NDP / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.2 Å
AuthorsXie, X. / Kulathila, R.
CitationJournal: ACS Med Chem Lett / Year: 2017
Title: Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1.
Authors: Levell, J.R. / Caferro, T. / Chenail, G. / Dix, I. / Dooley, J. / Firestone, B. / Fortin, P.D. / Giraldes, J. / Gould, T. / Growney, J.D. / Jones, M.D. / Kulathila, R. / Lin, F. / Liu, G. / ...Authors: Levell, J.R. / Caferro, T. / Chenail, G. / Dix, I. / Dooley, J. / Firestone, B. / Fortin, P.D. / Giraldes, J. / Gould, T. / Growney, J.D. / Jones, M.D. / Kulathila, R. / Lin, F. / Liu, G. / Mueller, A. / van der Plas, S. / Slocum, K. / Smith, T. / Terranova, R. / Toure, B.B. / Tyagi, V. / Wagner, T. / Xie, X. / Xu, M. / Yang, F.S. / Zhou, L.X. / Pagliarini, R. / Cho, Y.S.
History
DepositionOct 24, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 1, 2017Group: Database references
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isocitrate dehydrogenase [NADP] cytoplasmic
B: Isocitrate dehydrogenase [NADP] cytoplasmic
C: Isocitrate dehydrogenase [NADP] cytoplasmic
D: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)193,13416
Polymers187,6504
Non-polymers5,48412
Water11,422634
1
A: Isocitrate dehydrogenase [NADP] cytoplasmic
C: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,5678
Polymers93,8252
Non-polymers2,7426
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8560 Å2
ΔGint-49 kcal/mol
Surface area34840 Å2
MethodPISA
2
B: Isocitrate dehydrogenase [NADP] cytoplasmic
D: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,5678
Polymers93,8252
Non-polymers2,7426
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8480 Å2
ΔGint-50 kcal/mol
Surface area34290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.731, 155.745, 163.048
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
Isocitrate dehydrogenase [NADP] cytoplasmic / IDH / Cytosolic NADP-isocitrate dehydrogenase / IDP / NADP(+)-specific ICDH / Oxalosuccinate decarboxylase


Mass: 46912.391 Da / Num. of mol.: 4 / Mutation: R132H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IDH1, PICD / Production host: Escherichia coli (E. coli)
References: UniProt: O75874, isocitrate dehydrogenase (NADP+)
#2: Chemical
ChemComp-FLC / CITRATE ANION / Citric acid


Mass: 189.100 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H5O7
#3: Chemical
ChemComp-7J2 / (4S)-3-[2-({(1S)-1-[5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl]ethyl}amino)pyrimidin-4-yl]-4-(propan-2-yl)-1,3-oxazolidin-2-one


Mass: 436.482 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H25FN6O2
#4: Chemical
ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 634 / 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: 2.77 Å3/Da / Density % sol: 37.19 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop
Details: co-crystallization with protein concentration at 10mG/mL and compound at 250uM; reservoir solution contains 1.6M tri-ammonium citrate and 0.1M Bis-Tris (pH5.5)
Temp details: room temperature

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 26, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→163.05 Å / Num. obs: 106133 / % possible obs: 99.9 % / Redundancy: 6.6 % / Biso Wilson estimate: 50.45 Å2 / Rmerge(I) obs: 0.051 / Net I/σ(I): 20.7
Reflection shellResolution: 2.2→2.32 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.495 / Mean I/σ(I) obs: 3.5 / % possible all: 100

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Processing

Software
NameVersionClassificationNB
BUSTER-TNT2.11.6refinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
SCALAdata scaling
PHASERphasing
BUSTERrefinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.2→112.62 Å / Cor.coef. Fo:Fc: 0.9545 / Cor.coef. Fo:Fc free: 0.9392 / SU R Cruickshank DPI: 0.215 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.219 / SU Rfree Blow DPI: 0.178 / SU Rfree Cruickshank DPI: 0.178
RfactorNum. reflection% reflectionSelection details
Rfree0.2248 5295 4.99 %RANDOM
Rwork0.1875 ---
obs0.1894 106033 99.86 %-
Displacement parametersBiso max: 150.63 Å2 / Biso mean: 52.71 Å2 / Biso min: 20.19 Å2
Baniso -1Baniso -2Baniso -3
1--0.9196 Å20 Å20 Å2
2--1.2549 Å20 Å2
3----0.3353 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 2.2→112.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12822 0 372 634 13828
Biso mean--56.14 49.41 -
Num. residues----1618
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d4814SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes349HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1917HARMONIC5
X-RAY DIFFRACTIONt_it13525HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1752SEMIHARMONIC5
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_contact15864SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d13525HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg18291HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion3.17
X-RAY DIFFRACTIONt_other_torsion18.05
LS refinement shellResolution: 2.2→2.26 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2329 398 5.16 %
Rwork0.2107 7322 -
all0.2119 7720 -
obs--99.41 %

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