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- PDB-6o2z: Crystal structure of IDH1 R132H mutant in complex with compound 32 -

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Basic information

Entry
Database: PDB / ID: 6o2z
TitleCrystal structure of IDH1 R132H mutant in complex with compound 32
ComponentsIsocitrate dehydrogenase [NADP] cytoplasmic
KeywordsOxidoreductase/Inhibitor / IDH1 / allosteric inhibitor / Oxidoreductase / Inhibitor complex / Oxidoreductase-Inhibitor complex
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 / tricarboxylic acid cycle / glutathione metabolic process / Peroxisomal protein import / NAD binding / peroxisome / tertiary granule lumen / NADP binding / secretory granule lumen / ficolin-1-rich granule lumen / response to oxidative stress / 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-LJV / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsToms, A.V. / Lin, J.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Discovery and Optimization of Quinolinone Derivatives as Potent, Selective, and Orally Bioavailable Mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors.
Authors: Lin, J. / Lu, W. / Caravella, J.A. / Campbell, A.M. / Diebold, R.B. / Ericsson, A. / Fritzen, E. / Gustafson, G.R. / Lancia Jr., D.R. / Shelekhin, T. / Wang, Z. / Castro, J. / Clarke, A. / ...Authors: Lin, J. / Lu, W. / Caravella, J.A. / Campbell, A.M. / Diebold, R.B. / Ericsson, A. / Fritzen, E. / Gustafson, G.R. / Lancia Jr., D.R. / Shelekhin, T. / Wang, Z. / Castro, J. / Clarke, A. / Gotur, D. / Josephine, H.R. / Katz, M. / Diep, H. / Kershaw, M. / Yao, L. / Kauffman, G. / Hubbs, S.E. / Luke, G.P. / Toms, A.V. / Wang, L. / Bair, K.W. / Barr, K.J. / Dinsmore, C. / Walker, D. / Ashwell, S.
History
DepositionFeb 25, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 26, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Mar 13, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)98,5928
Polymers96,2712
Non-polymers2,3216
Water2,522140
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8500 Å2
ΔGint-49 kcal/mol
Surface area34070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.344, 82.344, 303.740
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein Isocitrate dehydrogenase [NADP] cytoplasmic / IDH / Cytosolic NADP-isocitrate dehydrogenase / IDP / NADP(+)-specific ICDH / Oxalosuccinate decarboxylase


Mass: 48135.684 Da / Num. of mol.: 2 / 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) / Strain (production host): Rosetta2(DE3)
References: UniProt: O75874, isocitrate dehydrogenase (NADP+)
#2: Chemical ChemComp-LJV / 6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methylpyridine-3-carbonitrile


Mass: 324.764 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H13ClN4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 140 / 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: 2.67 Å3/Da / Density % sol: 54 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 1.8 M Tri-ammonium citrate pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 4, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 37491 / % possible obs: 97 % / Redundancy: 8 % / Net I/σ(I): 16.3
Reflection shellResolution: 2.5→2.59 Å / Rmerge(I) obs: 0.607

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→46.25 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.921 / SU B: 8.532 / SU ML: 0.188 / Cross valid method: THROUGHOUT / ESU R: 0.393 / ESU R Free: 0.259 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23356 1894 5.1 %RANDOM
Rwork0.17195 ---
obs0.17511 35493 99.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 44.236 Å2
Baniso -1Baniso -2Baniso -3
1--0.38 Å20 Å20 Å2
2---0.38 Å20 Å2
3---0.77 Å2
Refinement stepCycle: 1 / Resolution: 2.5→46.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6480 0 154 140 6774
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0136778
X-RAY DIFFRACTIONr_bond_other_d0.0020.0176174
X-RAY DIFFRACTIONr_angle_refined_deg1.5371.6559165
X-RAY DIFFRACTIONr_angle_other_deg1.2741.58714366
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5235818
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.54423.735332
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.261151183
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.0911527
X-RAY DIFFRACTIONr_chiral_restr0.0690.2886
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.027504
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021379
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.3484.4663284
X-RAY DIFFRACTIONr_mcbond_other3.3344.4643283
X-RAY DIFFRACTIONr_mcangle_it4.9756.6874100
X-RAY DIFFRACTIONr_mcangle_other4.9766.6914100
X-RAY DIFFRACTIONr_scbond_it4.2225.0083494
X-RAY DIFFRACTIONr_scbond_other4.2215.0093495
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.5517.2985066
X-RAY DIFFRACTIONr_long_range_B_refined8.30351.3247446
X-RAY DIFFRACTIONr_long_range_B_other8.30151.3177437
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.5→2.56 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3 135 -
Rwork0.222 2530 -
obs--98.52 %

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