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- PDB-8bay: Crystal Structure of IDH1 variant R132C S280F in complex with NAD... -

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Basic information

Entry
Database: PDB / ID: 8bay
TitleCrystal Structure of IDH1 variant R132C S280F in complex with NADPH, Ca2+ and 3-butyl-2-oxoglutarate
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
Chem-NDP / (S)-3-butyl-2-oxopentanedioic acid / (R)-3-butyl-2-oxopentanedioic acid / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsRabe, P. / Schofield, C.J. / Reinbold, R. / Brewitz, L.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC)BB/V001892/1 United Kingdom
Wellcome Trust106244/Z/14/Z United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/R506655/1 United Kingdom
CitationJournal: J.Biol.Chem. / Year: 2023
Title: Natural and synthetic 2-oxoglutarate derivatives are substrates for oncogenic variants of human isocitrate dehydrogenase 1 and 2.
Authors: Liu, X. / Reinbold, R. / Liu, S. / Herold, R.A. / Rabe, P. / Duclos, S. / Yadav, R.B. / Abboud, M.I. / Thieffine, S. / Armstrong, F.A. / Brewitz, L. / Schofield, C.J.
History
DepositionOct 12, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 2, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 8, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Feb 22, 2023Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.3Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)147,42220
Polymers143,3923
Non-polymers4,03017
Water4,035224
1
A: Isocitrate dehydrogenase [NADP] cytoplasmic
B: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,25113
Polymers95,5952
Non-polymers2,65611
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9840 Å2
ΔGint-80 kcal/mol
Surface area31050 Å2
MethodPISA
2
C: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules

C: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,34314
Polymers95,5952
Non-polymers2,74812
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_575x,-y+2,-z1
Buried area9880 Å2
ΔGint-83 kcal/mol
Surface area32620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.540, 275.780, 116.610
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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Components

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Protein , 1 types, 3 molecules ABC

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


Mass: 47797.406 Da / Num. of mol.: 3 / Mutation: R132C, S280F
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+)

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Non-polymers , 6 types, 241 molecules

#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.: 3 / Source method: obtained synthetically / Formula: C21H30N7O17P3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-QDC / (R)-3-butyl-2-oxopentanedioic acid / (3~{R})-3-butyl-2-oxidanylidene-pentanedioic acid


Mass: 202.204 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C9H14O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-QD8 / (S)-3-butyl-2-oxopentanedioic acid / (3~{S})-3-butyl-2-oxidanylidene-pentanedioic acid


Mass: 202.204 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C9H14O5 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 224 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.85 Å3/Da / Density % sol: 56.78 % / Description: Plates, 100 um x 300 um
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 15-20 % PEG 3350, Calcium acetate hydrate, BISTRIS

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cryogenic / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97628 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jun 30, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97628 Å / Relative weight: 1
ReflectionResolution: 2.35→58.44 Å / Num. obs: 67110 / % possible obs: 100 % / Redundancy: 11.7 % / Biso Wilson estimate: 57.04 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.104 / Rpim(I) all: 0.032 / Rrim(I) all: 0.109 / Net I/σ(I): 14
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.35-2.4111.51.8071.248960.6030.5441.8999.5
10.51-58.4412.40.0368430.99999.2

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4KZO

4kzo


Resolution: 2.35→46.81 Å / SU ML: 0.34 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 25.85 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2229 3297 4.92 %
Rwork0.2007 63763 -
obs0.2018 67060 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 152.8 Å2 / Biso mean: 67.4305 Å2 / Biso min: 39.05 Å2
Refinement stepCycle: final / Resolution: 2.35→46.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9599 0 261 225 10085
Biso mean--77.74 61.61 -
Num. residues----1236
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 24

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.35-2.380.35661330.32792601273499
2.38-2.420.33251320.298326232755100
2.42-2.460.32511280.289926282756100
2.46-2.50.36451550.320226342789100
2.5-2.540.3361280.312426352763100
2.54-2.590.34851350.302426222757100
2.59-2.640.35881270.273326582785100
2.64-2.690.28421310.277226312762100
2.69-2.750.30471450.25426222767100
2.75-2.810.30291380.253126362774100
2.81-2.880.2771130.2526632776100
2.88-2.960.3091450.247126372782100
2.96-3.050.24661480.248526172765100
3.05-3.150.25721350.267226452780100
3.15-3.260.26771410.23226622803100
3.26-3.390.29931330.219526542787100
3.39-3.540.25511360.205126542790100
3.54-3.730.1911350.199726622797100
3.73-3.960.21161090.188727032812100
3.96-4.270.15911370.16326722809100
4.27-4.70.1641550.140226732828100
4.7-5.380.17991510.151726752826100
5.38-6.770.21561520.184827172869100
6.77-46.810.17011550.167628392994100
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)
10.6268-0.1270.42483.40710.33361.3677-0.11760.12680.1121-0.407-0.14250.0934-0.27790.03830.26250.617-0.0431-0.09790.41110.0660.587618.3183317.042534.6756
21.1624-0.85420.0312.946-0.95892.1456-0.14240.16420.41570.0939-0.16-0.6854-0.25840.4740.26340.4288-0.065-0.14390.45470.08750.703833.929310.185553.2041
31.6883-0.2768-0.51292.25380.40931.771-0.03470.13180.2008-0.5885-0.21650.1832-0.58110.00880.23420.9209-0.0466-0.27270.41020.09140.742916.2235330.958235.6452
42.4725-0.73320.53171.56060.5651.37530.1449-0.11-0.1214-0.3225-0.07080.0835-0.18970.09-0.06950.73890.0277-0.03840.3460.01570.481729.3057311.180980.2892
55.3161-2.4128-3.814.48831.80735.9805-0.09870.14410.00690.28020.1290.01920.4782-0.0581-0.02880.49380.0468-0.10620.42290.09340.528628.0627292.679756.3725
60.8925-0.1181-0.07071.0464-0.36622.282-0.1854-0.08910.01660.2980.0040.2202-0.2517-0.29040.13950.54110.0191-0.09960.39650.01130.629913.8908309.167161.7082
72.87180.9917-1.16648.8933-0.80533.25240.0089-0.20960.1379-1.03030.1704-0.6634-0.5370.1664-0.23920.81510.0004-0.00590.4241-0.04960.554824.6367324.926884.9399
82.3945-0.124-0.5161.09860.20171.63190.112-0.1910.32080.0842-0.0657-0.2584-0.3950.5347-0.05450.4013-0.1315-0.01060.60130.00130.472429.2913284.669921.9931
91.98760.6824-0.63130.5731-0.20911.1581-0.0868-0.1384-0.17240.02710.0256-0.07380.21910.04460.07210.40240.01-0.00390.47050.03870.47635.814267.3435.0975
104.7684-0.5982-0.1761.551-0.45362.9320.25550.11270.19970.041-0.13790.1008-0.20090.128-0.04970.4056-0.05730.02180.4336-0.03380.389615.1549283.902823.5994
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 3 through 133 )A3 - 133
2X-RAY DIFFRACTION2chain 'A' and (resid 134 through 284 )A134 - 284
3X-RAY DIFFRACTION3chain 'A' and (resid 285 through 416 )A285 - 416
4X-RAY DIFFRACTION4chain 'B' and (resid 3 through 133 )B3 - 133
5X-RAY DIFFRACTION5chain 'B' and (resid 134 through 164 )B134 - 164
6X-RAY DIFFRACTION6chain 'B' and (resid 165 through 296 )B165 - 296
7X-RAY DIFFRACTION7chain 'B' and (resid 297 through 415 )B297 - 415
8X-RAY DIFFRACTION8chain 'C' and (resid 3 through 133 )C3 - 133
9X-RAY DIFFRACTION9chain 'C' and (resid 134 through 285 )C134 - 285
10X-RAY DIFFRACTION10chain 'C' and (resid 286 through 417 )C286 - 417

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