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- PDB-6q6f: Crystal structure of IDH1 R132H in complex with HMS101 -

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Basic information

Entry
Database: PDB / ID: 6q6f
TitleCrystal structure of IDH1 R132H in complex with HMS101
ComponentsIsocitrate dehydrogenase [NADP] cytoplasmic
KeywordsOXIDOREDUCTASE / Inhibitor / Isocitrate Dehydrogenase / Mutant R132H / Cytoplasmic
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-HJQ / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.3 Å
AuthorsChaturvedi, A. / Goparaju, R. / Gupta, C. / Kluenemann, T. / Araujo Cruz, M.M. / Kloos, A. / Goerlich, K. / Schottmann, R. / Struys, E.A. / Ganser, A. ...Chaturvedi, A. / Goparaju, R. / Gupta, C. / Kluenemann, T. / Araujo Cruz, M.M. / Kloos, A. / Goerlich, K. / Schottmann, R. / Struys, E.A. / Ganser, A. / Preller, M. / Heuser, M.
CitationJournal: Leukemia / Year: 2020
Title: In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site.
Authors: Chaturvedi, A. / Goparaju, R. / Gupta, C. / Weder, J. / Klunemann, T. / Araujo Cruz, M.M. / Kloos, A. / Goerlich, K. / Schottmann, R. / Othman, B. / Struys, E.A. / Bahre, H. / Grote-Koska, D. ...Authors: Chaturvedi, A. / Goparaju, R. / Gupta, C. / Weder, J. / Klunemann, T. / Araujo Cruz, M.M. / Kloos, A. / Goerlich, K. / Schottmann, R. / Othman, B. / Struys, E.A. / Bahre, H. / Grote-Koska, D. / Brand, K. / Ganser, A. / Preller, M. / Heuser, M.
History
DepositionDec 10, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 16, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 12, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.2Jan 24, 2024Group: 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

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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)94,0134
Polymers93,4022
Non-polymers6112
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4860 Å2
ΔGint-37 kcal/mol
Surface area36890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.396, 82.396, 301.430
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Space group name HallP4nw2abw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+3/4
#3: y+1/2,-x+1/2,z+1/4
#4: x+1/2,-y+1/2,-z+1/4
#5: -x+1/2,y+1/2,-z+3/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

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


Mass: 46701.176 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 BL21(DE3) (bacteria)
References: UniProt: O75874, isocitrate dehydrogenase (NADP+)
#2: Chemical ChemComp-HJQ / (2~{R})-2-[2-[(3~{R})-3-(4-fluorophenyl)pyrrolidin-1-yl]ethyl]-1,4-dimethyl-piperazine


Mass: 305.433 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C18H28FN3 / Feature type: SUBJECT OF INVESTIGATION

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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: 2.74 Å3/Da / Density % sol: 55.09 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.2M di-ammonium citrate, 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 31, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.3→46.09 Å / Num. obs: 16362 / % possible obs: 95.67 % / Redundancy: 7 % / Rmerge(I) obs: 0.129 / Net I/σ(I): 16.47
Reflection shellResolution: 3.3→3.45 Å

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1T09

1t09


Resolution: 3.3→46.09 Å / SU ML: 0.4789 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 32.1719
RfactorNum. reflection% reflection
Rfree0.2885 798 5.06 %
Rwork0.2321 --
obs0.235 15771 95.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 79.85 Å2
Refinement stepCycle: LAST / Resolution: 3.3→46.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6475 0 0 0 6475
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01196614
X-RAY DIFFRACTIONf_angle_d1.31968917
X-RAY DIFFRACTIONf_chiral_restr0.0688960
X-RAY DIFFRACTIONf_plane_restr0.00811135
X-RAY DIFFRACTIONf_dihedral_angle_d3.6113949
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.3-3.510.40711270.3482278X-RAY DIFFRACTION90.96
3.51-3.780.33461190.31492400X-RAY DIFFRACTION93.4
3.78-4.160.30831310.26262271X-RAY DIFFRACTION89.06
4.16-4.760.28321260.19082595X-RAY DIFFRACTION100
4.76-5.990.26791470.21472627X-RAY DIFFRACTION99.96
5.99-46.10.25271480.20132802X-RAY DIFFRACTION99.59

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