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- EMDB-72964: Cryo-EM structure of IDH1 R132H -

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Basic information

Entry
Database: EMDB / ID: EMD-72964
TitleCryo-EM structure of IDH1 R132H
Map datastructure of IDH1 R132H
Sample
  • Complex: Human isocitrate dehydrogenase 1 R132H mutant
    • Protein or peptide: Isocitrate dehydrogenase [NADP] cytoplasmic
  • Ligand: NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
KeywordsDehydrogenase / cellular metabolism / oxidative decarboxylation / CYTOSOLIC PROTEIN
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 / NADPH regeneration / 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 / NADPH regeneration / 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 / response to oxidative stress / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.69 Å
AuthorsHu L / Seo H-S / Dhe-Paganon S / Berezuk AM / Tuttle KS / Zhu X / Subramaniam S / Wu X
Funding support Canada, 1 items
OrganizationGrant numberCountry
Canada Excellence Research Chair Award Canada
CitationJournal: Nat Chem Biol / Year: 2026
Title: Autopalmitoylation of IDH1-R132H regulates its neomorphic activity in cancer cells.
Authors: Lu Hu / Jinyu Lin / Liping Sun / Alison M Berezuk / Katharine S Tuttle / Xing Zhu / Hyuk-Soo Seo / Sirano Dhe-Paganon / Pan Li / Yang Sun / Lisheng Ni / Jianan Zhang / Dazhi Tan / Hiroaki ...Authors: Lu Hu / Jinyu Lin / Liping Sun / Alison M Berezuk / Katharine S Tuttle / Xing Zhu / Hyuk-Soo Seo / Sirano Dhe-Paganon / Pan Li / Yang Sun / Lisheng Ni / Jianan Zhang / Dazhi Tan / Hiroaki Wakimoto / Daniel P Cahill / Xiaochen Bai / Xuelian Luo / John M Asara / Sriram Subramaniam / Yibing Shan / Xu Wu /
Abstract: Gain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) lead to oncometabolite (R)-2-hydroxyglutarate production, contributing to the tumorigenesis of multiple human cancers. While fatty acid ...Gain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) lead to oncometabolite (R)-2-hydroxyglutarate production, contributing to the tumorigenesis of multiple human cancers. While fatty acid biosynthesis is critical for IDH1-mutant tumor growth, the underlying mechanisms remain unclear. Here, leveraging chemical probes and chemoproteomic profiling, we identified that oncogenic IDH1-R132H is uniquely autopalmitoylated at C269, which is not observed in wild-type IDH1. This modification responds to fatty acids and regulates R132H enzymatic activity by enhancing substrate and cofactor binding, as well as dimerization. Loss of C269 palmitoylation reverses IDH1-R132H-induced metabolic reprogramming and hypermethylation phenotypes and impairs cell transformation. Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical IDH1-mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the IDH1 mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in IDH1-mutant cancers.
History
DepositionSep 30, 2025-
Header (metadata) releaseFeb 4, 2026-
Map releaseFeb 4, 2026-
UpdateFeb 4, 2026-
Current statusFeb 4, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72964.png

Downloads & links

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Map

FileDownload / File: emd_72964.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationstructure of IDH1 R132H
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 256 pix.
= 256. Å		1 Å/pix.
x 256 pix.
= 256. Å		1 Å/pix.
x 256 pix.
= 256. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.19
Minimum - Maximum-0.39582193 - 0.8461454
Average (Standard dev.)-0.00038573827 (±0.0165877)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 256.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map A

Fileemd_72964_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_72964_half_map_2.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human isocitrate dehydrogenase 1 R132H mutant

EntireName: Human isocitrate dehydrogenase 1 R132H mutant
Components
  • Complex: Human isocitrate dehydrogenase 1 R132H mutant
    • Protein or peptide: Isocitrate dehydrogenase [NADP] cytoplasmic
  • Ligand: NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE

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Supramolecule #1: Human isocitrate dehydrogenase 1 R132H mutant

SupramoleculeName: Human isocitrate dehydrogenase 1 R132H mutant / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isocitrate dehydrogenase [NADP] cytoplasmic

MacromoleculeName: Isocitrate dehydrogenase [NADP] cytoplasmic / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: isocitrate dehydrogenase (NADP+)
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 47.859395 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSKKISGGSV VEMQGDEMTR IIWELIKEKL IFPYVELDLH SYDLGIENRD ATNDQVTKDA AEAIKKHNVG VKCATITPDE KRVEEFKLK QMWKSPNGTI RNILGGTVFR EAIICKNIPR LVSGWVKPII IGHHAYGDQY RATDFVVPGP GKVEITYTPS D GTQKVTYL ...String:
MSKKISGGSV VEMQGDEMTR IIWELIKEKL IFPYVELDLH SYDLGIENRD ATNDQVTKDA AEAIKKHNVG VKCATITPDE KRVEEFKLK QMWKSPNGTI RNILGGTVFR EAIICKNIPR LVSGWVKPII IGHHAYGDQY RATDFVVPGP GKVEITYTPS D GTQKVTYL VHNFEEGGGV AMGMYNQDKS IEDFAHSSFQ MALSKGWPLY LSTKNTILKK YDGRFKDIFQ EIYDKQYKSQ FE AQKIWYE HRLIDDMVAQ AMKSEGGFIW ACKNYDGDVQ SDSVAQGYGS LGMMTSVLVC PDGKTVEAEA AHGTVTRHYR MYQ KGQETS TNPIASIFAW TRGLAHRAKL DNNKELAFFA NALEEVSIET IEAGFMTKDL AACIKGLPNV QRSDYLNTFE FMDK LGENL KIKLAQAKLS LEHHHHHH

UniProtKB: Isocitrate dehydrogenase [NADP] cytoplasmic

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Macromolecule #2: NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE

MacromoleculeName: NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / type: ligand / ID: 2 / Number of copies: 2 / Formula: NAP
Molecular weightTheoretical: 743.405 Da
Chemical component information

ChemComp-NAP:
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.69 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 103976
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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