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- PDB-8vh9: Crystal Structure of Human IDH1 R132Q in complex with NADPH -

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Basic information

Entry
Database: PDB / ID: 8vh9
TitleCrystal Structure of Human IDH1 R132Q in complex with NADPH
ComponentsIsocitrate dehydrogenase [NADP] cytoplasmic
KeywordsOXIDOREDUCTASE
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 / Isocitrate/isopropylmalate dehydrogenase, conserved site / Isocitrate and isopropylmalate dehydrogenases signature. / Isopropylmalate dehydrogenase-like domain / Isocitrate/isopropylmalate dehydrogenase / Isocitrate/isopropylmalate dehydrogenase
Similarity search - Domain/homology
CITRIC ACID / Chem-NDP / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.13 Å
AuthorsMealka, M. / Sohl, C.D. / Huxford, T.
Funding support United States, 2items
OrganizationGrant numberCountry
American Cancer SocietyRSG-19-075-01-TBE United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R35 GM137773 United States
CitationJournal: Nat Commun / Year: 2024
Title: Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms.
Authors: Mealka, M. / Sierra, N.A. / Avellaneda Matteo, D. / Albekioni, E. / Khoury, R. / Mai, T. / Conley, B.M. / Coleman, N.J. / Sabo, K.A. / Komives, E.A. / Bobkov, A.A. / Cooksy, A.L. / Silletti, ...Authors: Mealka, M. / Sierra, N.A. / Avellaneda Matteo, D. / Albekioni, E. / Khoury, R. / Mai, T. / Conley, B.M. / Coleman, N.J. / Sabo, K.A. / Komives, E.A. / Bobkov, A.A. / Cooksy, A.L. / Silletti, S. / Schiffer, J.M. / Huxford, T. / Sohl, C.D.
History
DepositionDec 31, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 24, 2024Provider: repository / Type: Initial release
Revision 1.1May 22, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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)99,14410
Polymers97,0002
Non-polymers2,1438
Water6,179343
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7850 Å2
ΔGint-40 kcal/mol
Surface area35390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.085, 81.085, 306.136
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
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 / IDH1 / Cytosolic NADP-isocitrate dehydrogenase / IDPc / NADP(+)-specific ICDH / ...IDH / IDH1 / Cytosolic NADP-isocitrate dehydrogenase / IDPc / NADP(+)-specific ICDH / Oxalosuccinate decarboxylase


Mass: 48500.117 Da / Num. of mol.: 2 / Mutation: R132Q
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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 343 / 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: 2.6 Å3/Da / Density % sol: 52.7 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 200 mM ammonium citrate tribasic pH 7.0 and 26% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 21, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.13→78.38 Å / Num. obs: 108848 / % possible obs: 99.91 % / Redundancy: 8.9 % / Biso Wilson estimate: 44.62 Å2 / CC1/2: 0.999 / Net I/σ(I): 18.29
Reflection shellResolution: 2.13→2.19 Å / Num. unique obs: 4459 / CC1/2: 0.688

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.13→78.38 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.65 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2152 5441 5 %
Rwork0.1754 --
obs0.1774 108848 99.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.13→78.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6301 0 139 343 6783
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0096605
X-RAY DIFFRACTIONf_angle_d0.9998922
X-RAY DIFFRACTIONf_dihedral_angle_d9.194895
X-RAY DIFFRACTIONf_chiral_restr0.057963
X-RAY DIFFRACTIONf_plane_restr0.0081126
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.13-2.150.33472030.2993440X-RAY DIFFRACTION100
2.15-2.180.29261910.28863458X-RAY DIFFRACTION100
2.18-2.210.32521570.26993477X-RAY DIFFRACTION100
2.21-2.230.3252020.25853380X-RAY DIFFRACTION100
2.23-2.260.27091660.24543523X-RAY DIFFRACTION100
2.26-2.290.25871860.22353442X-RAY DIFFRACTION100
2.29-2.330.29421850.23273473X-RAY DIFFRACTION100
2.33-2.360.27081710.22073415X-RAY DIFFRACTION100
2.36-2.40.2511990.22253453X-RAY DIFFRACTION100
2.4-2.440.28171500.20523484X-RAY DIFFRACTION100
2.44-2.480.27141570.21263466X-RAY DIFFRACTION100
2.48-2.530.25681910.20963389X-RAY DIFFRACTION99
2.53-2.570.28342140.21433416X-RAY DIFFRACTION100
2.57-2.630.29621850.21443457X-RAY DIFFRACTION100
2.63-2.680.28182060.22113436X-RAY DIFFRACTION100
2.68-2.750.28311660.21063458X-RAY DIFFRACTION100
2.75-2.810.29511660.20773486X-RAY DIFFRACTION100
2.81-2.890.25441620.20293469X-RAY DIFFRACTION100
2.89-2.980.27331960.19583414X-RAY DIFFRACTION100
2.98-3.070.22372020.18873452X-RAY DIFFRACTION100
3.07-3.180.20431670.183447X-RAY DIFFRACTION100
3.18-3.310.2122330.18483368X-RAY DIFFRACTION100
3.31-3.460.20091890.18923429X-RAY DIFFRACTION99
3.46-3.640.21151540.16183465X-RAY DIFFRACTION99
3.64-3.870.18191790.14763463X-RAY DIFFRACTION100
3.87-4.170.21371790.14473420X-RAY DIFFRACTION100
4.17-4.590.14481650.12853484X-RAY DIFFRACTION100
4.59-5.250.15371840.12673431X-RAY DIFFRACTION100
5.25-6.610.18571750.16473451X-RAY DIFFRACTION100
6.62-78.380.17861610.15793461X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 8.8275 Å / Origin y: -34.3814 Å / Origin z: 1.4702 Å
111213212223313233
T0.3561 Å20.0215 Å2-0.0169 Å2-0.3184 Å20.0056 Å2--0.3917 Å2
L0.0753 °20.0633 °20.0956 °2--0.0231 °2-0.0682 °2--0.3648 °2
S0.002 Å °0.0034 Å °-0.0083 Å °0.006 Å °-0.0285 Å °0.0141 Å °-0.0132 Å °0.0044 Å °0.0297 Å °
Refinement TLS groupSelection details: all

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