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

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Basic information

Entry
Database: PDB / ID: 7pjn
TitleCrystal Structure of Ivosidenib-resistant IDH1 variant R132C S280F in complex with NADPH and inhibitor DS-1001B
Components(Isocitrate dehydrogenase [NADP] ...) x 2
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-7SU / CITRIC ACID / Chem-NDP / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsReinbold, R. / Rabe, P. / Abboud, M.I. / Schofield, C.J. / Clifton, I.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 1.3Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / 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
D: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)197,86023
Polymers191,2224
Non-polymers6,63819
Water1,946108
1
A: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules

D: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,91811
Polymers95,5952
Non-polymers3,3239
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_554x,y,z-11
Buried area8820 Å2
ΔGint-52 kcal/mol
Surface area32680 Å2
MethodPISA
2
B: Isocitrate dehydrogenase [NADP] cytoplasmic
C: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,94212
Polymers95,6272
Non-polymers3,31510
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8930 Å2
ΔGint-51 kcal/mol
Surface area32680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.180, 153.050, 164.010
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Isocitrate dehydrogenase [NADP] ... , 2 types, 4 molecules ACDB

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


Mass: 47829.406 Da / Num. of mol.: 1
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 , 5 types, 127 molecules

#3: Chemical
ChemComp-7SU / (E)-3-(1-(5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)isoxazole-4-carbonyl)-3-methyl-1H-indol-4-yl)acrylic acid / (2E)-3-(1-{[5-(2-Fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoic acid


Mass: 535.779 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H18Cl3FN2O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C6H8O7
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical
ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H30N7O17P3 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 108 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.63 Å3/Da / Density % sol: 53.26 % / Description: rectangle, 100x100
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 2 M Ammonium citrate tribasic, DTT 2 mM

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cryo / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9999 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Nov 27, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.45→55.95 Å / Num. obs: 74987 / % possible obs: 100 % / Redundancy: 13.7 % / CC1/2: 1 / Rmerge(I) obs: 0.092 / Rpim(I) all: 0.026 / Rrim(I) all: 0.096 / Net I/σ(I): 18.9 / Num. measured all: 1025494
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
2.45-2.5113.32.217256854700.5130.6192.2971.299.7
10.96-55.95120.0211147695710.0060.02272.999.2

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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: 5TQH

5tqh


Resolution: 2.45→55.36 Å / SU ML: 0.36 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 26.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2284 3675 4.91 %
Rwork0.1856 71202 -
obs0.1877 74877 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 182.14 Å2 / Biso mean: 81.1665 Å2 / Biso min: 41.84 Å2
Refinement stepCycle: final / Resolution: 2.45→55.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12372 0 668 109 13149
Biso mean--83.24 64.13 -
Num. residues----1623
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 26

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.45-2.480.35541330.3092692282599
2.48-2.520.30591510.294227022853100
2.52-2.550.37241170.281727252842100
2.55-2.590.35911550.274626902845100
2.59-2.630.36951080.281927102818100
2.63-2.670.29861170.275427702887100
2.67-2.720.34331270.262826862813100
2.72-2.770.30951410.251127462887100
2.77-2.820.28751580.249826452803100
2.82-2.880.31531380.24427652903100
2.88-2.940.30481440.23726942838100
2.94-3.010.28421610.237726792840100
3.01-3.090.291150.235327842899100
3.09-3.170.28781250.223627082833100
3.17-3.260.26271360.231427392875100
3.26-3.370.25131690.201326842853100
3.37-3.490.24931360.192127552891100
3.49-3.630.23111320.182527382870100
3.63-3.790.22221630.166427072870100
3.79-3.990.20081570.165527452902100
3.99-4.240.19281480.150227612909100
4.24-4.570.19711340.133527592893100
4.57-5.030.16141410.135227762917100
5.03-5.760.19361810.166127632944100
5.76-7.250.24011370.188828392976100
7.25-55.360.19181510.171729403091100
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)
11.8421-0.80531.08191.7787-0.41761.75480.0119-0.1250.0617-0.20320.0280.00010.0884-0.0309-0.06060.517-0.01870.00390.48440.0070.470839.128-10.839-17.4802
26.82372.451-2.36621.6046-1.67745.3741-0.32150.29820.4631-0.43330.0922-0.23940.1730.02370.25330.63630.11710.04670.49370.09540.676841.7473-39.0209-40.1465
31.87532.2916-0.19128.10750.48491.4432-0.03280.21190.1327-0.36530.14860.805-0.2690.044-0.12570.48640.0175-0.06420.4460.08610.464723.4387-18.4697-36.1971
42.74790.2358-0.37451.993-0.72382.0519-0.0990.12360.41-0.09470.0910.1361-0.1985-0.153-0.00440.53420.0117-0.06770.4682-0.00990.474735.351.5857-21.2926
51.5368-0.49640.80672.0677-0.93812.2964-0.031-0.0406-0.01860.0386-0.0079-0.03-0.0493-0.010.03210.4326-0.0369-0.01060.48050.01510.450947.9674-18.62358.5585
60.88030.02411.53848.12443.32816.99470.0964-0.08740.35390.1729-0.380.34840.074-0.50220.32390.3606-0.0206-0.01190.67250.03420.774419.3225-21.012632.828
73.52152.757-1.03144.8201-0.6311.6730.1572-0.1354-0.27810.0999-0.19470.05950.16190.00930.01680.4390.0195-0.04120.45530.02630.46643.5382-33.320824.7272
81.7742-0.04391.05462.5136-0.48713.2408-0.06380.18170.0040.0652-0.1212-0.5074-0.13430.61970.14110.42260.01690.01130.66750.10.570263.6028-20.434211.6663
92.70560.16730.08021.6134-0.41583.19910.1175-0.3934-0.37940.2546-0.11820.57480.1408-0.54380.01010.6539-0.08340.09050.6613-0.05780.742942.9043-21.780860.041
102.83662.38071.20175.43912.74512.22240.0904-0.11620.29770.22590.12780.2149-0.147-0.1676-0.24460.4279-0.02380.04490.5570.03630.566724.2123-16.800635.6102
117.5927-0.9571-0.65380.32770.07814.7781-0.0789-0.06660.7530.06650.09980.1256-0.42930.1639-0.02150.5383-0.02950.00560.4243-0.01360.705842.9687-6.595637.7241
123.7573-1.5234-0.88062.14410.8212.1786-0.0208-0.1672-0.45260.0919-0.02040.2520.32940.05410.03250.6417-0.06180.02620.5465-0.02030.571956.3302-20.96458.8952
132.079-0.3925-0.67162.93540.53463.0842-0.31770.2254-0.7888-0.2162-0.01930.50550.4597-0.22330.31040.7005-0.05190.14050.5381-0.09660.754537.3678-16.362895.1989
145.4345-0.8363-1.85231.22992.23374.1071-0.44520.07620.0446-0.3547-0.01-0.26670.09010.33010.4340.54750.02770.03350.4410.12880.600541.3693-38.4267124.4496
151.16-0.52121.46193.8735-0.47372.6922-0.0960.08030.1451-0.1787-0.069-0.6386-0.17050.31170.14990.6337-0.02730.1430.65670.05940.690750.345-14.5671113.1768
167.0263-4.0336-4.16625.04962.8134.88830.29390.7079-0.0435-0.7002-0.31130.4013-0.7556-0.32970.01660.794-0.02050.02020.4950.03590.489735.113-0.825694.724
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 3 through 132 )A3 - 132
2X-RAY DIFFRACTION2chain 'A' and (resid 133 through 185 )A133 - 185
3X-RAY DIFFRACTION3chain 'A' and (resid 186 through 287 )A186 - 287
4X-RAY DIFFRACTION4chain 'A' and (resid 288 through 412 )A288 - 412
5X-RAY DIFFRACTION5chain 'B' and (resid 2 through 132 )B2 - 132
6X-RAY DIFFRACTION6chain 'B' and (resid 133 through 185 )B133 - 185
7X-RAY DIFFRACTION7chain 'B' and (resid 186 through 312 )B186 - 312
8X-RAY DIFFRACTION8chain 'B' and (resid 313 through 411 )B313 - 411
9X-RAY DIFFRACTION9chain 'C' and (resid 3 through 132 )C3 - 132
10X-RAY DIFFRACTION10chain 'C' and (resid 133 through 203 )C133 - 203
11X-RAY DIFFRACTION11chain 'C' and (resid 204 through 285 )C204 - 285
12X-RAY DIFFRACTION12chain 'C' and (resid 286 through 415 )C286 - 415
13X-RAY DIFFRACTION13chain 'D' and (resid 2 through 132 )D2 - 132
14X-RAY DIFFRACTION14chain 'D' and (resid 133 through 185 )D133 - 185
15X-RAY DIFFRACTION15chain 'D' and (resid 186 through 312 )D186 - 312
16X-RAY DIFFRACTION16chain 'D' and (resid 313 through 413 )D313 - 413

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