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- PDB-6vg0: CRYSTAL STRUCTURE OF HUMAN CYTOSOLIC ISOCITRATE DEHYDROGENASE (ID... -

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Basic information

Entry
Database: PDB / ID: 6vg0
TitleCRYSTAL STRUCTURE OF HUMAN CYTOSOLIC ISOCITRATE DEHYDROGENASE (IDH1) R132H MUTANT IN COMPLEX WITH NADPH and AGI-15056
ComponentsIsocitrate dehydrogenase [NADP] cytoplasmic
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE inhibitor / IDH / CYTOSOLIC NADP-ISOCITRATE DEHYDROGENASE / OXALOSUCCINATE DECARBOXYLASE / NADP(+)-SPECIFIC ICDH / IDP / OXIDOREDUCTASE-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 / NADP+ metabolic process / 2-oxoglutarate 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 / NADP+ metabolic process / 2-oxoglutarate metabolic process / glyoxylate cycle / response to steroid hormone / female gonad development / peroxisomal matrix / tricarboxylic acid cycle / glutathione metabolic process / Peroxisomal protein import / NAD binding / tertiary granule lumen / peroxisome / 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-NDP / Chem-QWM / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.66 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 7, 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
C: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)147,4288
Polymers144,4073
Non-polymers3,0215
Water1,76598
1
A: Isocitrate dehydrogenase [NADP] cytoplasmic
B: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,1555
Polymers96,2712
Non-polymers1,8833
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8230 Å2
ΔGint-53 kcal/mol
Surface area33860 Å2
MethodPISA
2
C: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules

C: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,5476
Polymers96,2712
Non-polymers2,2764
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,-y,z1
Buried area8500 Å2
ΔGint-51 kcal/mol
Surface area34440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)196.770, 89.160, 90.750
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
Components on special symmetry positions
IDModelComponents
11C-501-

QWM

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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.: 3
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


Mass: 745.421 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical ChemComp-QWM / N~2~,N~4~-bis[(1R)-1-cyclopropylethyl]-6-[6-(trifluoromethyl)pyridin-2-yl]-1,3,5-triazine-2,4-diamine


Mass: 392.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H23F3N6 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 98 / Source method: isolated from a natural source / Formula: H2O
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: 2.76 Å3/Da / Density % sol: 55.38 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 0.25 M ammonium sulfate, 0.1M sodium citrate pH 5.6, 23% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 23, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.66→41.2 Å / Num. obs: 45671 / % possible obs: 98.1 % / Redundancy: 5 % / Biso Wilson estimate: 42.85 Å2 / Rmerge(I) obs: 0.101 / Net I/σ(I): 15.8
Reflection shellResolution: 2.66→2.73 Å / Rmerge(I) obs: 0.694 / Num. unique obs: 3370

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Processing

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

3inm


Resolution: 2.66→41.2 Å / SU ML: 0.4066 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 26.4807
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2643 2305 5.05 %Random selection
Rwork0.2064 43299 --
obs0.2093 45604 97.75 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 48.68 Å2
Refinement stepCycle: LAST / Resolution: 2.66→41.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9757 0 200 98 10055
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00210265
X-RAY DIFFRACTIONf_angle_d0.492213891
X-RAY DIFFRACTIONf_chiral_restr0.04081498
X-RAY DIFFRACTIONf_plane_restr0.00291810
X-RAY DIFFRACTIONf_dihedral_angle_d18.2863859
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.66-2.720.32051300.26292722X-RAY DIFFRACTION99.93
2.72-2.780.32111420.2722742X-RAY DIFFRACTION99.86
2.78-2.850.33751560.27432705X-RAY DIFFRACTION99.93
2.85-2.930.34761430.2622730X-RAY DIFFRACTION99.9
2.93-3.010.29531430.25992731X-RAY DIFFRACTION99.83
3.01-3.110.3651350.25332733X-RAY DIFFRACTION99.76
3.11-3.220.29611490.24432724X-RAY DIFFRACTION99.41
3.22-3.350.32561530.24042714X-RAY DIFFRACTION98.96
3.35-3.50.29191390.23012714X-RAY DIFFRACTION98.86
3.5-3.690.27191440.20732700X-RAY DIFFRACTION98.1
3.69-3.920.26881460.19792696X-RAY DIFFRACTION97.53
3.92-4.220.22911550.18552649X-RAY DIFFRACTION95.99
4.22-4.650.20961410.16332656X-RAY DIFFRACTION95.4
4.65-5.320.19651410.16262670X-RAY DIFFRACTION94.61
5.32-6.690.22941480.18582684X-RAY DIFFRACTION94.97
6.69-41.20.23691400.172729X-RAY DIFFRACTION91.78

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