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- PDB-5i95: Crystal Structure of Human Mitochondrial Isocitrate Dehydrogenase... -

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Basic information

Entry
Database: PDB / ID: 5i95
TitleCrystal Structure of Human Mitochondrial Isocitrate Dehydrogenase R140Q Mutant Homodimer bound to NADPH and alpha-Ketoglutaric acid
ComponentsIsocitrate dehydrogenase [NADP], mitochondrial
KeywordsOXIDOREDUCTASE / IDH / ICD-M / IDP NADP(+)-specific ICDH Oxalosuccinate decarboxylase / aKG / alphaKG / oxo-glutarate.
Function / homology
Function and homology information


Citric acid cycle (TCA cycle) / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / isocitrate dehydrogenase (NADP+) activity / 2-oxoglutarate metabolic process / NADP metabolic process / glyoxylate cycle / tricarboxylic acid cycle / Transcriptional activation of mitochondrial biogenesis / peroxisome ...Citric acid cycle (TCA cycle) / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / isocitrate dehydrogenase (NADP+) activity / 2-oxoglutarate metabolic process / NADP metabolic process / glyoxylate cycle / tricarboxylic acid cycle / Transcriptional activation of mitochondrial biogenesis / peroxisome / NAD binding / carbohydrate metabolic process / mitochondrial matrix / magnesium ion binding / mitochondrion / extracellular exosome / 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
ACETATE ION / 2-OXOGLUTARIC ACID / Chem-NDP / Isocitrate dehydrogenase [NADP], mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.54 Å
AuthorsZhang, B. / Jin, L. / Wu, W. / Jiang, F. / DeLaBarre, B. / Travins, J.A. / Padyana, A.K.
Citation
Journal: Cancer Discov / Year: 2017
Title: AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations.
Authors: Yen, K. / Travins, J. / Wang, F. / David, M.D. / Artin, E. / Straley, K. / Padyana, A. / Gross, S. / DeLaBarre, B. / Tobin, E. / Chen, Y. / Nagaraja, R. / Choe, S. / Jin, L. / Konteatis, Z. ...Authors: Yen, K. / Travins, J. / Wang, F. / David, M.D. / Artin, E. / Straley, K. / Padyana, A. / Gross, S. / DeLaBarre, B. / Tobin, E. / Chen, Y. / Nagaraja, R. / Choe, S. / Jin, L. / Konteatis, Z. / Cianchetta, G. / Saunders, J.O. / Salituro, F.G. / Quivoron, C. / Opolon, P. / Bawa, O. / Saada, V. / Paci, A. / Broutin, S. / Bernard, O.A. / de Botton, S. / Marteyn, B.S. / Pilichowska, M. / Xu, Y. / Fang, C. / Jiang, F. / Wei, W. / Jin, S. / Silverman, L. / Liu, W. / Yang, H. / Dang, L. / Dorsch, M. / Penard-Lacronique, V. / Biller, S.A. / Su, S.M.
#1: Journal: Science / Year: 2013
Title: Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation
Authors: Wang, F. / Travins, J. / DeLaBarre, B. / Penard-Lacronique, V. / Schalm, S. / Hansen, E. / Straley, K. / Kernytsky, A. / Liu, W. / Gliser, C. / Yang, H. / Gross, S. / Artin, E. / Saada, V. / ...Authors: Wang, F. / Travins, J. / DeLaBarre, B. / Penard-Lacronique, V. / Schalm, S. / Hansen, E. / Straley, K. / Kernytsky, A. / Liu, W. / Gliser, C. / Yang, H. / Gross, S. / Artin, E. / Saada, V. / Mylonas, E. / Quivoron, C. / Popovici-Muller, J. / Saunders, J.O. / Salituro, F.G. / Yan, S. / Murray, S. / Wei, W. / Gao, Y. / Dang, L. / Dorsch, M. / Agresta, S. / Schenkein, D.P. / Biller, S.A. / Su, S.M. / de Botton, S. / Yen, K.E.
History
DepositionFeb 19, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 1, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 8, 2017Group: Structure summary
Revision 1.2May 10, 2017Group: Database references
Revision 1.3Jul 5, 2017Group: Database references / Structure summary / Category: entity / struct_ref_seq_dif / Item: _entity.pdbx_mutation / _struct_ref_seq_dif.details
Revision 1.4Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_alt_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_label_alt_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_alt_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_ptnr1_label_alt_id / _struct_conn.pdbx_ptnr2_label_alt_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_symmetry

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isocitrate dehydrogenase [NADP], mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,4909
Polymers48,1311
Non-polymers1,3598
Water10,611589
1
A: Isocitrate dehydrogenase [NADP], mitochondrial
hetero molecules

A: Isocitrate dehydrogenase [NADP], mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,98018
Polymers96,2622
Non-polymers2,71816
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_454-x-1,y,-z-1/21
Buried area14150 Å2
ΔGint-90 kcal/mol
Surface area30320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.178, 154.875, 93.570
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-1188-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Isocitrate dehydrogenase [NADP], mitochondrial / IDH / ICD-M / IDP / NADP(+)-specific ICDH / Oxalosuccinate decarboxylase


Mass: 48130.855 Da / Num. of mol.: 1 / Fragment: UNP residues 40-452 / Mutation: R140Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IDH2 / Plasmid: pET-41a(+) / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P48735, isocitrate dehydrogenase (NADP+)

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Non-polymers , 6 types, 597 molecules

#2: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#6: Chemical ChemComp-AKG / 2-OXOGLUTARIC ACID / Α-Ketoglutaric acid


Mass: 146.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H6O5
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 589 / 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: 2.61 Å3/Da / Density % sol: 52.8 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 200 mM magnesium acetate, 100 mM sodium cacodylate, pH 6.5, 20% PEG8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97916 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97916 Å / Relative weight: 1
ReflectionResolution: 1.54→29.83 Å / Num. obs: 72657 / % possible obs: 99.5 % / Redundancy: 4.8 % / Rmerge(I) obs: 0.078 / Χ2: 1.054 / Net I/av σ(I): 19.495 / Net I/σ(I): 10.5 / Num. measured all: 350607
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
1.54-1.64.30.534198.3
1.6-1.664.80.4199.5
1.66-1.734.80.306199.5
1.73-1.834.90.222199.8
1.83-1.944.80.182199.9
1.94-2.094.90.119199.9
2.09-2.34.90.0851100
2.3-2.6350.0681100
2.63-3.3250.0761100
3.32-504.80.037198.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
HKL-2000data scaling
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4JA8

4ja8


Resolution: 1.54→29.83 Å / Cor.coef. Fo:Fc: 0.976 / Cor.coef. Fo:Fc free: 0.965 / SU B: 1.243 / SU ML: 0.044 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.063 / ESU R Free: 0.067 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1742 3624 5 %RANDOM
Rwork0.1422 ---
obs0.1438 68300 99.37 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 74.4 Å2 / Biso mean: 17.449 Å2 / Biso min: 4.28 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å2-0 Å2
2--0 Å20 Å2
3----0 Å2
Refinement stepCycle: final / Resolution: 1.54→29.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3281 0 88 591 3960
Biso mean--19.22 33.71 -
Num. residues----413
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0260.0193634
X-RAY DIFFRACTIONr_bond_other_d0.0020.023470
X-RAY DIFFRACTIONr_angle_refined_deg2.4311.9734936
X-RAY DIFFRACTIONr_angle_other_deg1.36238033
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2815458
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.89324.303165
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.93315656
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1461521
X-RAY DIFFRACTIONr_chiral_restr0.1470.2534
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.024105
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02840
X-RAY DIFFRACTIONr_mcbond_it1.5971.3471730
X-RAY DIFFRACTIONr_mcbond_other1.5921.3451728
X-RAY DIFFRACTIONr_mcangle_it2.2772.0162182
LS refinement shellResolution: 1.54→1.58 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.262 262 -
Rwork0.243 4965 -
all-5227 -
obs--98.64 %

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