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- PDB-6b0z: IDH1 R132H mutant in complex with IDH305 -

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Basic information

Entry
Database: PDB / ID: 6b0z
TitleIDH1 R132H mutant in complex with IDH305
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-C81 / CITRATE ANION / Chem-NDP / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.334 Å
AuthorsXie, X. / Kulathila, R.
CitationJournal: ACS Med Chem Lett / Year: 2017
Title: Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor.
Authors: Cho, Y.S. / Levell, J.R. / Liu, G. / Caferro, T. / Sutton, J. / Shafer, C.M. / Costales, A. / Manning, J.R. / Zhao, Q. / Sendzik, M. / Shultz, M. / Chenail, G. / Dooley, J. / Villalba, B. / ...Authors: Cho, Y.S. / Levell, J.R. / Liu, G. / Caferro, T. / Sutton, J. / Shafer, C.M. / Costales, A. / Manning, J.R. / Zhao, Q. / Sendzik, M. / Shultz, M. / Chenail, G. / Dooley, J. / Villalba, B. / Farsidjani, A. / Chen, J. / Kulathila, R. / Xie, X. / Dodd, S. / Gould, T. / Liang, G. / Heimbach, T. / Slocum, K. / Firestone, B. / Pu, M. / Pagliarini, R. / Growney, J.D.
History
DepositionSep 15, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 8, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)194,33018
Polymers187,6504
Non-polymers6,68114
Water9,206511
1
A: Isocitrate dehydrogenase [NADP] cytoplasmic
C: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,1659
Polymers93,8252
Non-polymers3,3407
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8590 Å2
ΔGint-50 kcal/mol
Surface area33860 Å2
MethodPISA
2
B: Isocitrate dehydrogenase [NADP] cytoplasmic
D: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,1659
Polymers93,8252
Non-polymers3,3407
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8480 Å2
ΔGint-48 kcal/mol
Surface area34260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.495, 155.312, 163.054
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-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
#3: Chemical
ChemComp-C81 / (4R)-4-[(1S)-1-fluoroethyl]-3-[2-({(1S)-1-[4-methyl-2'-(trifluoromethyl)[3,4'-bipyridin]-6-yl]ethyl}amino)pyrimidin-4-yl]-1,3-oxazolidin-2-one


Mass: 490.453 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C23H22F4N6O2
#4: Chemical
ChemComp-FLC / CITRATE ANION / Citric acid


Mass: 189.100 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H5O7
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 511 / 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: 2.75 Å3/Da / Density % sol: 55.27 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: co-crystallization of protein (20-24mG/mL) /compound complex at 1/1.5 molar ratio; reservoir solution: 1.5-1.8M Tri Ammonium Citrate, 0.1M Bis-Tris pH6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 X 6M / Detector: PIXEL / Date: Jun 19, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.334→163.054 Å / Num. obs: 584723 / % possible obs: 100 % / Redundancy: 6.6 % / Net I/σ(I): 15

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Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
PDB_EXTRACT3.22data extraction
XDSdata processing
autoPROCdata scaling
PHASERphasing
RefinementResolution: 2.334→43.704 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.44
RfactorNum. reflection% reflection
Rfree0.2352 4444 5.01 %
Rwork0.1888 --
obs0.1912 88623 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 107.21 Å2 / Biso mean: 48.3298 Å2 / Biso min: 20.39 Å2
Refinement stepCycle: final / Resolution: 2.334→43.704 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12802 0 454 511 13767
Biso mean--52.69 42.6 -
Num. residues----1617
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00313583
X-RAY DIFFRACTIONf_angle_d0.70818386
X-RAY DIFFRACTIONf_chiral_restr0.0471976
X-RAY DIFFRACTIONf_plane_restr0.0042311
X-RAY DIFFRACTIONf_dihedral_angle_d13.7610342
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3336-2.36010.28921640.243327752939100
2.3601-2.38790.29061190.243727972916100
2.3879-2.4170.29841780.240427472925100
2.417-2.44760.31051430.23527722915100
2.4476-2.47980.30141490.228727612910100
2.4798-2.51380.33341490.234627382887100
2.5138-2.54970.31921340.231228572991100
2.5497-2.58770.26971390.227927712910100
2.5877-2.62820.27491290.223328132942100
2.6282-2.67120.26311370.222627282865100
2.6712-2.71730.26141520.222328172969100
2.7173-2.76670.29611420.219627462888100
2.7667-2.81990.30291400.226828112951100
2.8199-2.87740.26691490.227327782927100
2.8774-2.940.28561500.231527822932100
2.94-3.00840.26811420.224628132955100
3.0084-3.08360.27561420.225427922934100
3.0836-3.16690.28441490.22128152964100
3.1669-3.26010.26511500.213927872937100
3.2601-3.36530.2581610.206227842945100
3.3653-3.48550.23991510.193827652916100
3.4855-3.6250.24891430.182828342977100
3.625-3.78990.21671670.172627972964100
3.7899-3.98960.21261570.162128092966100
3.9896-4.23940.21851680.158328092977100
4.2394-4.56640.19771470.147628302977100
4.5664-5.02530.17681460.143928573003100
5.0253-5.75110.19411370.166228673004100
5.7511-7.24040.21711430.182729153058100
7.2404-43.71130.17891670.1653012317999

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