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- PDB-5lge: Crystal Structure of human IDH1 mutant (R132H) in complex with NA... -

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Basic information

Entry
Database: PDB / ID: 5lge
TitleCrystal Structure of human IDH1 mutant (R132H) in complex with NADP+ and an Inhibitor related to BAY 1436032
ComponentsIsocitrate dehydrogenase [NADP] cytoplasmic
KeywordsOXIDOREDUCTASE / IDH1 / ALLOSTERIC INHIBITOR / NADP+
Function / homology
Function and homology information


Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate / NADPH regeneration / NFE2L2 regulating TCA cycle genes / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / NADPH regeneration / isocitrate dehydrogenase (NADP+) activity / NADP+ metabolic process / 2-oxoglutarate metabolic process / glyoxylate cycle ...Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate / NADPH regeneration / NFE2L2 regulating TCA cycle genes / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / NADPH regeneration / 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 / Peroxisomal protein import / NAD binding / NADP binding / tertiary granule lumen / peroxisome / secretory granule lumen / 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-6VN / ACETATE ION / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsHillig, R.C. / Hars, U. / Korndoerfer, I.P.
CitationJournal: Acta Neuropathol. / Year: 2017
Title: Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo.
Authors: Pusch, S. / Krausert, S. / Fischer, V. / Balss, J. / Ott, M. / Schrimpf, D. / Capper, D. / Sahm, F. / Eisel, J. / Beck, A.C. / Jugold, M. / Eichwald, V. / Kaulfuss, S. / Panknin, O. / ...Authors: Pusch, S. / Krausert, S. / Fischer, V. / Balss, J. / Ott, M. / Schrimpf, D. / Capper, D. / Sahm, F. / Eisel, J. / Beck, A.C. / Jugold, M. / Eichwald, V. / Kaulfuss, S. / Panknin, O. / Rehwinkel, H. / Zimmermann, K. / Hillig, R.C. / Guenther, J. / Toschi, L. / Neuhaus, R. / Haegebart, A. / Hess-Stumpp, H. / Bauser, M. / Wick, W. / Unterberg, A. / Herold-Mende, C. / Platten, M. / von Deimling, A.
History
DepositionJul 7, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 8, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2017Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _citation.country / _database_2.pdbx_DOI ..._citation.country / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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
D: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)196,60114
Polymers192,5434
Non-polymers4,05810
Water9,206511
1
A: Isocitrate dehydrogenase [NADP] cytoplasmic
B: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,2406
Polymers96,2712
Non-polymers1,9684
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8180 Å2
ΔGint-47 kcal/mol
Surface area33660 Å2
MethodPISA
2
C: Isocitrate dehydrogenase [NADP] cytoplasmic
D: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,3618
Polymers96,2712
Non-polymers2,0906
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8780 Å2
ΔGint-45 kcal/mol
Surface area34500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.900, 110.320, 198.540
Angle α, β, γ (deg.)90.00, 91.19, 90.00
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: LYS / Beg label comp-ID: LYS / Refine code: _

Dom-IDEns-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LEULEUAA3 - 4163 - 416
21LEULEUBB3 - 4163 - 416
12LEULEUAA3 - 4163 - 416
22LEULEUCC3 - 4163 - 416
13SERSERAA3 - 4153 - 415
23SERSERDD3 - 4153 - 415
14LEULEUBB3 - 4163 - 416
24LEULEUCC3 - 4163 - 416
15SERSERBB3 - 4153 - 415
25SERSERDD3 - 4153 - 415
16LEULEUCC3 - 4143 - 414
26LEULEUDD3 - 4143 - 414

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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Protein , 1 types, 4 molecules ABCD

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


Mass: 48135.684 Da / Num. of mol.: 4 / Mutation: R132H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IDH1, PICD / Plasmid: P10T7-2 / Production host: Escherichia coli (E. coli) / Variant (production host): RIL
References: UniProt: O75874, isocitrate dehydrogenase (NADP+)

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Non-polymers , 5 types, 521 molecules

#2: Chemical
ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-6VN / 2-[(4-propan-2-ylphenyl)amino]-1-[(1~{S},5~{S})-3,3,5-trimethylcyclohexyl]benzimidazole-5-carboxylic acid


Mass: 419.559 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H33N3O2
#5: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#6: Water ChemComp-HOH / 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: 2.76 Å3/Da / Density % sol: 55.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7
Details: PROTEIN BUFFER: 15 MG/ML. PROTEIN IN 25 MM HEPES, 300 MM NACL, 5 MM BETA-ME, COMPLETE PROTEASE INHIBITOR MIXTURE, PH 7.7 RESERVOIR: 100 MM BIS-TRIS, PH 7.0, 200 MM CA-ACETATE, 20.0 %(W/V) PEG 3350

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Dec 16, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.7→30 Å / Num. obs: 56625 / % possible obs: 98.7 % / Observed criterion σ(I): 2 / Redundancy: 4.8 % / Rmerge(I) obs: 0.12 / Net I/σ(I): 8.6
Reflection shellResolution: 2.7→2.85 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.7 / Mean I/σ(I) obs: 2.3 / % possible all: 99

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4KZO

4kzo


Resolution: 2.7→29.94 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.927 / SU B: 25.881 / SU ML: 0.276 / Cross valid method: THROUGHOUT / ESU R Free: 0.321 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22977 2839 5 %RANDOM
Rwork0.19546 ---
obs0.19722 53784 98.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 73.2 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å20 Å20.48 Å2
2---0.43 Å2-0 Å2
3---0.44 Å2
Refinement stepCycle: 1 / Resolution: 2.7→29.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12995 0 270 511 13776
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.01913592
X-RAY DIFFRACTIONr_bond_other_d0.0050.0212869
X-RAY DIFFRACTIONr_angle_refined_deg1.4841.97118371
X-RAY DIFFRACTIONr_angle_other_deg1.3173.00129610
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.31951640
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.60624.821616
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.938152420
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.5561557
X-RAY DIFFRACTIONr_chiral_restr0.0790.21978
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0215185
X-RAY DIFFRACTIONr_gen_planes_other0.0030.023098
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_it1.5324.4216560
X-RAY DIFFRACTIONr_mcbond_other1.5324.4196557
X-RAY DIFFRACTIONr_mcangle_it2.7186.6188183
X-RAY DIFFRACTIONr_mcangle_other2.7186.6188184
X-RAY DIFFRACTIONr_scbond_it1.4544.6247032
X-RAY DIFFRACTIONr_scbond_other1.4544.6247033
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.5716.87610182
X-RAY DIFFRACTIONr_long_range_B_refined5.96735.60915363
X-RAY DIFFRACTIONr_long_range_B_other5.8935.5115249
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A485140.08
12B485140.08
21A495100.06
22C495100.06
31A491140.07
32D491140.07
41B495700.07
42C495700.07
51B497040.07
52D497040.07
61C503400.06
62D503400.06
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.328 209 -
Rwork0.316 3925 -
obs--98.95 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.94730.1584-0.35391.67190.32842.4948-0.07-0.2215-0.06140.2503-0.06250.34360.3195-0.4840.13250.0998-0.08350.03550.2443-0.05330.152-26.982-80.44629.314
21.48550.0711-0.03621.95450.10792.56960.0962-0.26510.28190.3495-0.0149-0.3886-0.15060.536-0.08130.135-0.1047-0.09110.2823-0.03720.1709-29.234-115.96227.326
31.3562-0.41260.81361.306-0.34762.70.05150.0060.1058-0.156-0.05660.2205-0.0064-0.58240.00510.07470.0533-0.070.3197-0.04010.1003-24.548-62.85572.279
41.2823-0.1288-0.19691.57460.39931.7045-0.09110.1758-0.0205-0.28120.0079-0.17950.07140.41020.08320.21890.1227-0.02560.28830.04410.1264-26.671-28.15267.381
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A3 - 416
2X-RAY DIFFRACTION2B3 - 416
3X-RAY DIFFRACTION3C2 - 416
4X-RAY DIFFRACTION4D3 - 416

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