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- PDB-36td: Crystal Structure of IDH2 (R172K) in complex with covalent inhibi... -

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Basic information

Entry
Database: PDB / ID: 36td
TitleCrystal Structure of IDH2 (R172K) in complex with covalent inhibitor LY3410738
ComponentsIsocitrate dehydrogenase [NADP], mitochondrial
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / IDH1 / IDH2 / Covalent / Inhibitor / LY3410738 / OXIDOREDUCTASE / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of glial cell migration / negative regulation of matrix metallopeptidase secretion / Citric acid cycle (TCA cycle) / Maturation of TCA enzymes and regulation of TCA cycle / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / isocitrate dehydrogenase (NADP+) activity / NADP+ metabolic process / NADP+ biosynthetic process / 2-oxoglutarate metabolic process ...negative regulation of glial cell migration / negative regulation of matrix metallopeptidase secretion / Citric acid cycle (TCA cycle) / Maturation of TCA enzymes and regulation of TCA cycle / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / isocitrate dehydrogenase (NADP+) activity / NADP+ metabolic process / NADP+ biosynthetic process / 2-oxoglutarate metabolic process / glyoxylate cycle / negative regulation of glial cell proliferation / tricarboxylic acid cycle / Mitochondrial protein degradation / Transcriptional activation of mitochondrial biogenesis / NAD binding / peroxisome / carbohydrate metabolic process / mitochondrial matrix / magnesium ion binding / mitochondrion / extracellular exosome / 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
: / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Isocitrate dehydrogenase [NADP], mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsAntonysamy, S.S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: LY3410738, a Covalent Inhibitor of Mutant IDH1/2, is Effective in Acute Myeloid Leukemia Preclinical Models
Authors: Antonysamy, S.S.
History
DepositionJun 30, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 22, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isocitrate dehydrogenase [NADP], mitochondrial
B: Isocitrate dehydrogenase [NADP], mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,7515
Polymers103,9952
Non-polymers1,7573
Water7,332407
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7290 Å2
ΔGint-60 kcal/mol
Surface area33670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.121, 112.501, 124.498
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Isocitrate dehydrogenase [NADP], mitochondrial / IDH / ICD-M / IDP / NADP(+)-specific ICDH / Oxalosuccinate decarboxylase


Mass: 51997.293 Da / Num. of mol.: 2 / Mutation: R172K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IDH2 / Production host: Escherichia coli (E. coli)
References: UniProt: P48735, isocitrate dehydrogenase (NADP+)
#2: Chemical ChemComp-A1DLL / 7-{[(1S)-1-{4-[(1S)-2-cyclopropyl-1-(4-propanoylpiperazin-1-yl)ethyl]phenyl}ethyl]amino}-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one / 7-{[(1S)-1-{4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl}ethyl]amino}-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one bound form


Mass: 506.640 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H38N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 407 / Source method: isolated from a natural source / Formula: H2O
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

Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 100mM Tris pH 8.5, 25% PEG 3350, 200mM Sodium Chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.984 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 7, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.984 Å / Relative weight: 1
ReflectionResolution: 2→19.7 Å / Num. obs: 53256 / % possible obs: 96.3 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.17 / Net I/σ(I): 3.1
Reflection shellResolution: 2→2.05 Å / Rmerge(I) obs: 0.859 / Num. unique obs: 7726

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→19.71 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.937 / SU R Cruickshank DPI: 0.232 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.24 / SU Rfree Blow DPI: 0.179 / SU Rfree Cruickshank DPI: 0.178
RfactorNum. reflection% reflectionSelection details
Rfree0.241 2610 -RANDOM
Rwork0.2142 50077 --
obs0.2155 52687 95.8 %-
Displacement parametersBiso mean: 36.91 Å2
Baniso -1Baniso -2Baniso -3
1-3.1423 Å20 Å20 Å2
2---3.3496 Å20 Å2
3---0.2073 Å2
Refine analyzeLuzzati coordinate error obs: 0.273 Å
Refinement stepCycle: LAST / Resolution: 2→19.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6467 0 122 407 6996
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0086825HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.969315HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2402SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1187HARMONIC5
X-RAY DIFFRACTIONt_it6665HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion880SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact5845SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.24
X-RAY DIFFRACTIONt_other_torsion16.79
LS refinement shellResolution: 2→2.01 Å
RfactorNum. reflection% reflection
Rfree0.3846 65 -
Rwork0.3219 989 -
obs0.3256 1054 96.73 %
Refinement TLS params.

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)
10.3111-0.1043-0.21170.12540.06790.5699-0.020.0762-0.12910.05290.01430.0819-0.03640.04420.0057-0.06170.01510.0116-0.017-0.01370.02072.0533-12.916712.8165
20.1024-0.0171-0.22750.03730.02650.4654-0.015-0.02980.0308-0.0130.0490.0498-0.01590.1034-0.0341-0.031-0.01040.01940.0189-0.0005-0.017720.290917.516319.0709
300.43082.91040.976-0.06130-0.0090.12860.0439-0.0086-0.02410.01590.0983-0.02490.033-0.02910.00990.06360.0178-0.0136-0.004512.7142.765210.8599
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A43 - 451
2X-RAY DIFFRACTION2{ B|* }B41 - 451
3X-RAY DIFFRACTION3(CHAIN A AND RESID 501) OR (CHAIN B AND RESID 501)A - B501

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