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- PDB-7pjm: Crystal Structure of Ivosidenib-resistant IDH1 variant R132C S280... -

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Basic information

Entry
Database: PDB / ID: 7pjm
TitleCrystal Structure of Ivosidenib-resistant IDH1 variant R132C S280F in complex with NADPH and Ca2+/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 / 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
2-OXOGLUTARIC ACID / Chem-NDP / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsReinbold, R. / Rabe, P. / Abboud, M.I. / Schofield, C.J.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Wellcome Trust106244/Z/14/Z United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/R506655/1 United Kingdom
CitationJournal: Nat Commun / Year: 2022
Title: Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors.
Authors: Reinbold, R. / Hvinden, I.C. / Rabe, P. / Herold, R.A. / Finch, A. / Wood, J. / Morgan, M. / Staudt, M. / Clifton, I.J. / Armstrong, F.A. / McCullagh, J.S.O. / Redmond, J. / Bardella, C. / ...Authors: Reinbold, R. / Hvinden, I.C. / Rabe, P. / Herold, R.A. / Finch, A. / Wood, J. / Morgan, M. / Staudt, M. / Clifton, I.J. / Armstrong, F.A. / McCullagh, J.S.O. / Redmond, J. / Bardella, C. / Abboud, M.I. / Schofield, C.J.
History
DepositionAug 24, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 13, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 19, 2022Group: 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
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / Item: _pdbx_entry_details.has_protein_modification

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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)146,66219
Polymers143,3923
Non-polymers3,27016
Water6,143341
1
A: Isocitrate dehydrogenase [NADP] cytoplasmic
B: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,71312
Polymers95,5952
Non-polymers2,11810
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11720 Å2
ΔGint-97 kcal/mol
Surface area29520 Å2
MethodPISA
2
C: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules

C: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,89714
Polymers95,5952
Non-polymers2,30212
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_554x,-y,-z-11
Buried area11940 Å2
ΔGint-93 kcal/mol
Surface area28960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.580, 273.010, 117.420
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11C-1398-

HOH

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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, 357 molecules

#2: Chemical ChemComp-AKG / 2-OXOGLUTARIC ACID


Mass: 146.098 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C5H6O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#4: 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
#5: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 341 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.7 Å3/Da / Density % sol: 54.43 % / Description: Plates, 100x300
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting 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: cryo / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 17, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.1→71.95 Å / Num. obs: 90634 / % possible obs: 100 % / Redundancy: 13.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.105 / Rpim(I) all: 0.03 / Rrim(I) all: 0.11 / Net I/σ(I): 13.4 / Num. measured all: 1194768 / Scaling rejects: 2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.1-2.1512.72.378387465910.550.6862.4691.199.9
9.39-71.9511.40.0411294511400.9990.0120.04340.499.8

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.27data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4KZO

4kzo


Resolution: 2.1→59.01 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 23.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2098 4466 4.93 %
Rwork0.1805 86109 -
obs0.1819 90575 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 185.55 Å2 / Biso mean: 65.7665 Å2 / Biso min: 35.23 Å2
Refinement stepCycle: final / Resolution: 2.1→59.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9616 0 336 341 10293
Biso mean--71.72 54.67 -
Num. residues----1241
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.1-2.120.37921600.332827882948
2.12-2.150.36071550.302828342989
2.15-2.180.29781500.275528392989
2.18-2.20.30371490.264228563005
2.2-2.230.28971410.253728392980
2.23-2.260.30741310.252828642995
2.26-2.290.25971550.248328422997
2.29-2.330.27711470.233628192966
2.33-2.370.27741420.226628552997
2.37-2.40.23511460.234128663012
2.4-2.450.23571360.22328362972
2.45-2.490.24611430.218528893032
2.49-2.540.21171580.209828573015
2.54-2.590.23791220.213828672989
2.59-2.650.25541470.2128212968
2.65-2.710.23311570.202328453002
2.71-2.780.24561510.204728683019
2.78-2.850.2431690.209628473016
2.85-2.930.24771360.20928763012
2.93-3.030.24131460.216628713017
3.03-3.140.26821740.203228433017
3.14-3.260.19581460.190728703016
3.26-3.410.1961580.185228603018
3.41-3.590.19641450.181229063051
3.59-3.820.22071390.166929013040
3.82-4.110.16531330.146629073040
4.11-4.520.17381580.124129153073
4.52-5.180.14621510.126429173068
5.18-6.520.22781520.166729533105
6.52-59.010.18541690.17730583227
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)
11.87630.18360.33952.6786-0.44451.4115-0.04850.2090.1036-0.2402-0.1433-0.2431-0.14650.1060.18370.4737-0.01-0.01830.31580.01570.360918.733139.9683-26.6851
21.0589-0.52230.11983.6416-0.54681.2628-0.0512-0.0070.32520.0642-0.2344-0.4469-0.26150.39190.25950.3515-0.0576-0.08890.39260.06390.470233.130434.5334-7.3517
32.4577-0.0098-0.41912.3697-0.09091.611-0.01080.05780.3302-0.1896-0.1738-0.2928-0.31260.08210.1570.5382-0.0377-0.08250.27880.05810.426617.640153.986-26.6915
41.6889-1.06690.50144.59821.14862.1153-0.1499-0.33670.0660.73070.0477-0.01260.1780.09330.10410.7664-0.0110.0130.4873-0.02890.446626.350637.108518.6648
51.1057-1.29820.33613.13460.44091.5239-0.1078-0.21120.01690.256-0.15190.4141-0.1007-0.18540.25910.4315-0.0113-0.00140.3918-0.06520.534514.621330.3762-1.8455
61.9063-0.6699-0.6666.78180.11991.7175-0.1113-0.39160.20640.2378-0.0073-0.3321-0.10850.04210.08560.8008-0.0250.00030.5378-0.15770.525923.214150.108220.6262
71.3628-0.0355-0.8691.76940.68892.62150.0739-0.49070.20150.3383-0.28790.2257-0.14250.00170.21270.4023-0.11770.02390.5119-0.13380.410928.59747.7458-37.2606
82.73940.8087-1.26062.0732-0.17421.8316-0.064-0.2228-0.1370.1559-0-0.02410.1830.15830.08780.27550.0182-0.02990.3971-0.01340.334745.3962-3.9355-54.4871
93.7579-0.1236-0.4041.5450.33472.1088-0.0369-0.109-0.43740.1665-0.19870.27550.4153-0.28110.27870.3806-0.06170.05570.3776-0.09470.483126.9407-12.8238-53.8685
101.87360.41190.13121.79240.0971.79360.0587-0.33380.16550.296-0.37310.5151-0.0762-0.38930.22010.407-0.10710.18130.5788-0.29010.568115.08216.8566-36.188
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 285 )A134 - 285
3X-RAY DIFFRACTION3chain 'A' and (resid 286 through 417 )A286 - 417
4X-RAY DIFFRACTION4chain 'B' and (resid 2 through 133 )B2 - 133
5X-RAY DIFFRACTION5chain 'B' and (resid 134 through 285 )B134 - 285
6X-RAY DIFFRACTION6chain 'B' and (resid 286 through 413 )B286 - 413
7X-RAY DIFFRACTION7chain 'C' and (resid 3 through 133 )C3 - 133
8X-RAY DIFFRACTION8chain 'C' and (resid 134 through 203 )C134 - 203
9X-RAY DIFFRACTION9chain 'C' and (resid 204 through 285 )C204 - 285
10X-RAY DIFFRACTION10chain 'C' and (resid 286 through 416 )C286 - 416

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