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- PDB-6vei: Crystal Structure of Human Cytosolic Isocitrate Dehydrogenase (ID... -

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Basic information

Entry
Database: PDB / ID: 6vei
TitleCrystal Structure of Human Cytosolic Isocitrate Dehydrogenase (IDH1) R132H Mutant in Complex with NADPH and AG-881 (Vorasidenib) Inhibitor
ComponentsIsocitrate dehydrogenase [NADP] cytoplasmic
KeywordsANTITUMOR PROTEIN / IDH / CYTOSOLIC NADP-ISOCITRATE DEHYDROGENASE / OXALOSUCCINATE DECARBOXYLASE / NADP(+)-SPECIFIC ICDH / IDP
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 / peroxisome / NAD binding / 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 / cytoplasm / cytosol
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-33O / Chem-9UO / ACETATE ION / MALONIC ACID / D-MALATE / Chem-NDP / DI(HYDROXYETHYL)ETHER / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsPadyana, A. / Jin, L.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma.
Authors: Konteatis, Z. / Artin, E. / Nicolay, B. / Straley, K. / Padyana, A.K. / Jin, L. / Chen, Y. / Narayaraswamy, R. / Tong, S. / Wang, F. / Zhou, D. / Cui, D. / Cai, Z. / Luo, Z. / Fang, C. / ...Authors: Konteatis, Z. / Artin, E. / Nicolay, B. / Straley, K. / Padyana, A.K. / Jin, L. / Chen, Y. / Narayaraswamy, R. / Tong, S. / Wang, F. / Zhou, D. / Cui, D. / Cai, Z. / Luo, Z. / Fang, C. / Tang, H. / Lv, X. / Nagaraja, R. / Yang, H. / Su, S.M. / Sui, Z. / Dang, L. / Yen, K. / Popovici-Muller, J. / Codega, P. / Campos, C. / Mellinghoff, I.K. / Biller, S.A.
History
DepositionJan 2, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 5, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,58514
Polymers96,2712
Non-polymers3,31412
Water11,494638
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)117.213, 85.099, 96.663
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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Components

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Protein , 1 types, 2 molecules AB

#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
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+)

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Non-polymers , 9 types, 650 molecules

#2: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-33O / 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxaoctatriacontane-1,38-diol / Tridecaethyleneglycol


Mass: 590.699 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H54O14
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#7: Chemical ChemComp-MLA / MALONIC ACID / DICARBOXYLIC ACID C3 / PROPANEDIOLIC ACID / METHANEDICARBOXYLIC ACID


Mass: 104.061 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H4O4
#8: Chemical ChemComp-9UO / 6-(6-chloropyridin-2-yl)-N2,N4-bis[(2R)-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine


Mass: 414.737 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H13ClF6N6 / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical ChemComp-MLT / D-MALATE / (2R)-2-HYDROXYBUTANEDIOIC ACID / 2-HYDROXY-SUCCINIC ACID


Mass: 134.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O5
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 638 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.5 Å3/Da / Density % sol: 50.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4 / Details: 20% PEG 3350, 8% Tacsimate pH 4.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17B1 / Wavelength: 0.97915 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 4, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 57133 / % possible obs: 99.8 % / Redundancy: 7.1 % / Biso Wilson estimate: 27.15 Å2 / Rmerge(I) obs: 0.101 / Net I/σ(I): 9.5
Reflection shellResolution: 2.1→2.14 Å / Redundancy: 7.2 % / Rmerge(I) obs: 0.476 / Num. unique obs: 2817 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3INM

3inm


Resolution: 2.1→35.51 Å / SU ML: 0.183 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 17.7263
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.1952 2886 5.06 %Random selection
Rwork0.1575 54098 --
obs0.1594 56984 99.78 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 29.6 Å2
Refinement stepCycle: LAST / Resolution: 2.1→35.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6579 0 216 638 7433
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0027119
X-RAY DIFFRACTIONf_angle_d0.4679643
X-RAY DIFFRACTIONf_chiral_restr0.04051042
X-RAY DIFFRACTIONf_plane_restr0.00281263
X-RAY DIFFRACTIONf_dihedral_angle_d13.63321118
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.130.22271310.16432514X-RAY DIFFRACTION98.8
2.13-2.170.21851470.15782546X-RAY DIFFRACTION100
2.17-2.210.20961330.16012538X-RAY DIFFRACTION100
2.21-2.250.21671590.16252521X-RAY DIFFRACTION99.96
2.25-2.30.20981100.16612617X-RAY DIFFRACTION99.96
2.3-2.350.2331230.16912528X-RAY DIFFRACTION99.89
2.35-2.40.21911350.17372544X-RAY DIFFRACTION99.93
2.4-2.460.22611410.16772542X-RAY DIFFRACTION99.85
2.46-2.530.20431480.17542546X-RAY DIFFRACTION99.85
2.53-2.60.19311270.17992562X-RAY DIFFRACTION99.78
2.6-2.690.23221440.1752552X-RAY DIFFRACTION99.78
2.69-2.790.19711480.17672544X-RAY DIFFRACTION99.59
2.79-2.90.22861500.17652545X-RAY DIFFRACTION99.74
2.9-3.030.19751330.17782581X-RAY DIFFRACTION99.85
3.03-3.190.20061510.16592550X-RAY DIFFRACTION99.82
3.19-3.390.1881350.15672599X-RAY DIFFRACTION99.74
3.39-3.650.17721390.14722581X-RAY DIFFRACTION99.89
3.65-4.020.1771250.13782640X-RAY DIFFRACTION99.93
4.02-4.60.16151400.12822608X-RAY DIFFRACTION99.82
4.6-5.790.18141390.14232656X-RAY DIFFRACTION99.96
5.79-35.510.18871280.16262784X-RAY DIFFRACTION99.32
Refinement TLS params.Method: refined / Origin x: 32.8781702682 Å / Origin y: 21.6314184266 Å / Origin z: 28.2429674266 Å
111213212223313233
T0.205045877392 Å2-0.0109032817641 Å2-0.00950996198603 Å2-0.166570269394 Å20.00478446079054 Å2--0.168270453778 Å2
L0.804989791451 °2-0.160718199645 °2-0.0882628235788 °2-0.158482248292 °20.0305552516126 °2--0.141170398591 °2
S-0.00718431931427 Å °0.00143772786657 Å °0.00872494318302 Å °-0.00991660409879 Å °0.00351536541278 Å °-0.00131992987994 Å °-0.0349348084057 Å °-0.0181433014538 Å °0.00266576422078 Å °
Refinement TLS groupSelection details: all

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