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

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Basic information

Entry
Database: PDB / ID: 8vhc
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 / NAD binding / peroxisome / 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 / cytosol / cytoplasm
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
Chem-NDP / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.44 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)98,8678
Polymers97,0002
Non-polymers1,8676
Water1,35175
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7430 Å2
ΔGint-83 kcal/mol
Surface area35860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.884, 82.884, 303.926
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 / 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.: 2 / 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 75 / 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: 2.72 Å3/Da / Density % sol: 54.8 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 100mM Bis-Tris, 220mM Ammonium Sulfate, and 20%(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: 2.44→79.96 Å / Num. obs: 80846 / % possible obs: 99.6 % / Redundancy: 2 % / Biso Wilson estimate: 63.91 Å2 / CC1/2: 0.999 / Net I/σ(I): 22.37
Reflection shellResolution: 2.44→2.53 Å / Num. unique obs: 3910 / CC1/2: 0.621

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.44→79.96 Å / SU ML: 0.3852 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 26.9
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2401 3638 4.85 %
Rwork0.1922 71370 -
obs0.1946 75008 99.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 73.98 Å2
Refinement stepCycle: LAST / Resolution: 2.44→79.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6295 0 118 75 6488
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00216547
X-RAY DIFFRACTIONf_angle_d0.568842
X-RAY DIFFRACTIONf_chiral_restr0.0394956
X-RAY DIFFRACTIONf_plane_restr0.00271111
X-RAY DIFFRACTIONf_dihedral_angle_d6.3808876
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.44-2.470.39521400.33682718X-RAY DIFFRACTION98.96
2.47-2.510.35911430.31882754X-RAY DIFFRACTION99.69
2.51-2.540.36011250.28682679X-RAY DIFFRACTION97.39
2.54-2.580.34781220.28532769X-RAY DIFFRACTION99.69
2.58-2.620.34931450.27442712X-RAY DIFFRACTION99.76
2.62-2.660.29681290.27052791X-RAY DIFFRACTION99.73
2.66-2.710.29891300.25662720X-RAY DIFFRACTION99.75
2.71-2.760.32411270.25882812X-RAY DIFFRACTION99.9
2.76-2.810.35451450.26242700X-RAY DIFFRACTION99.86
2.81-2.870.34961550.27912765X-RAY DIFFRACTION99.76
2.87-2.930.35541340.28762764X-RAY DIFFRACTION99.79
2.93-30.36861310.29572748X-RAY DIFFRACTION99.9
3-3.070.35441360.26612766X-RAY DIFFRACTION99.86
3.07-3.160.28311570.23352730X-RAY DIFFRACTION100
3.16-3.250.24561370.21552755X-RAY DIFFRACTION99.9
3.25-3.350.27511260.2172779X-RAY DIFFRACTION99.9
3.35-3.470.2591690.20942704X-RAY DIFFRACTION99.93
3.47-3.610.27431240.21832773X-RAY DIFFRACTION99.72
3.61-3.780.24251340.18262763X-RAY DIFFRACTION98.87
3.78-3.980.22081370.16332717X-RAY DIFFRACTION99.93
3.98-4.230.20611500.16032744X-RAY DIFFRACTION99.9
4.23-4.550.18631450.14382739X-RAY DIFFRACTION99.79
4.55-5.010.18431720.142729X-RAY DIFFRACTION99.9
5.01-5.730.20211710.16092709X-RAY DIFFRACTION99.9
5.74-7.230.19441310.18262761X-RAY DIFFRACTION99.72
7.23-79.960.21771230.15082769X-RAY DIFFRACTION99.42
Refinement TLS params.Method: refined / Origin x: 31.2945543855 Å / Origin y: -6.14009953667 Å / Origin z: 1.84638738573 Å
111213212223313233
T0.562003984957 Å20.0176981866144 Å20.0340541054054 Å2-0.49139906829 Å20.0135982372302 Å2--0.559147428798 Å2
L0.0651756570361 °20.0711249325787 °2-0.0605560352962 °2-0.0406930649038 °20.13019819077 °2--0.652625612737 °2
S-0.0318701408966 Å °-0.00918106331138 Å °-0.00576134188212 Å °-0.0371718683918 Å °-0.0319828054408 Å °0.0160332430427 Å °0.0362840052331 Å °0.0324605087139 Å °0.0681280937305 Å °
Refinement TLS groupSelection details: all

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