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- PDB-36uj: Crystal Structure of IDH1 (R132H) in complex with covalent inhibi... -

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Basic information

Entry
Database: PDB / ID: 36uj
TitleCrystal Structure of IDH1 (R132H) in complex with covalent inhibitor LY3410738
ComponentsIsocitrate dehydrogenase [NADP] cytoplasmic
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / IDH1 / IDH2 / Covalent / Inhibitor / LY3410738 / OXIDOREDUCTASE / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate / NADPH regeneration / NFE2L2 regulating TCA cycle genes / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / NADPH regeneration / isocitrate dehydrogenase (NADP+) activity / NADP+ metabolic process / 2-oxoglutarate metabolic process / glyoxylate cycle ...Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate / NADPH regeneration / NFE2L2 regulating TCA cycle genes / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / NADPH regeneration / 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 / Peroxisomal protein import / NAD binding / NADP binding / tertiary granule lumen / peroxisome / secretory granule lumen / 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 / Isocitrate/isopropylmalate dehydrogenase, conserved site / Isocitrate and isopropylmalate dehydrogenases signature. / Isopropylmalate dehydrogenase-like domain / Isocitrate/isopropylmalate dehydrogenase / Isocitrate/isopropylmalate dehydrogenase
Similarity search - Domain/homology
: / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.442 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
DepositionJul 1, 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

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)96,9466
Polymers95,8012
Non-polymers1,1454
Water4,378243
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4320 Å2
ΔGint-55 kcal/mol
Surface area35780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.742, 82.742, 299.379
Angle α, β, γ (deg.)90, 90, 90
Int Tables number96
Space group name H-MP43212

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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: 47900.445 Da / Num. of mol.: 2 / Mutation: R132H
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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: 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
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 243 / 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

CrystalDensity Matthews: 2.67 Å3/Da / Density % sol: 54.01 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop
Details: 100mM Bis Tris pH 5, 5% DMSO, 22% PEG 3350, 200mM Ammonium Sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.9793 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Aug 2, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.442→20 Å / Num. obs: 36110 / % possible obs: 97.5 % / Redundancy: 10.4 % / Rmerge(I) obs: 0.12 / Net I/σ(I): 13.2
Reflection shellResolution: 2.442→2.57 Å / Rmerge(I) obs: 0.82 / Num. unique obs: 5461

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.442→19.56 Å / Cor.coef. Fo:Fc: 0.925 / Cor.coef. Fo:Fc free: 0.911 / SU R Cruickshank DPI: 0.395 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.416 / SU Rfree Blow DPI: 0.26 / SU Rfree Cruickshank DPI: 0.258
RfactorNum. reflection% reflectionSelection details
Rfree0.2572 1977 -RANDOM
Rwork0.2259 36669 --
obs0.2275 38646 97.4 %-
Displacement parametersBiso mean: 49.5 Å2
Baniso -1Baniso -2Baniso -3
1-0.32 Å20 Å20 Å2
2--0.32 Å20 Å2
3----0.64 Å2
Refine analyzeLuzzati coordinate error obs: 0.344 Å
Refinement stepCycle: LAST / Resolution: 2.442→19.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6100 0 80 243 6423
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0066390HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.868732HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2188SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1120HARMONIC5
X-RAY DIFFRACTIONt_it6390HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion843SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4951SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.82
X-RAY DIFFRACTIONt_other_torsion17.58
LS refinement shellResolution: 2.442→2.46 Å
RfactorNum. reflection% reflection
Rfree0.3128 45 -
Rwork0.29 728 -
obs--97.74 %
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)
11.6845-0.41-0.389200.16760.8884-0.0639-0.1832-0.10410.0492-0.0270.07510.0922-0.08820.09080.033-0.04220.0139-0.0822-0.0322-0.096249.69453.083-14.7373
21.92060.59780.56540.76110.08650.8632-0.22990.1820.4906-0.21560.02650.0903-0.22620.00520.20340.0035-0.0348-0.0532-0.05210.0193-0.029153.7319.835218.9916
301.6052-0.93061.08984.48070-0.0005-0.24380.2874-0.42690.0042-0.1041-0.00630.1303-0.00380.2958-0.1505-0.05620.24990.0288-0.058256.23877.80531.8365
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A3 - 415
2X-RAY DIFFRACTION2{ B|* }B0 - 415
3X-RAY DIFFRACTION3{ I|* }I1 - 2

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