9YHB

Cryo-EM structure of IDH1 R132H C269S

Summary for 9YHB

• Entry DOI: 10.2210/pdb9yhb/pdb
• EMDB information: 72965
• Descriptor: Isocitrate dehydrogenase [NADP] cytoplasmic, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (2 entities in total)
• Functional Keywords: dehydrogenase, cellular metabolism, oxidative decarboxylation, cytosolic protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 97173.47

Authors

Hu, L.,Seo, H.-S.,Dhe-Paganon, S.,Berezuk, A.M.,Tuttle, K.S.,Zhu, X.,Subramaniam, S.,Wu, X. (deposition date: 2025-09-30, release date: 2026-02-04)

Primary citation

Hu, L.,Lin, J.,Sun, L.,Berezuk, A.M.,Tuttle, K.S.,Zhu, X.,Seo, H.S.,Dhe-Paganon, S.,Li, P.,Sun, Y.,Ni, L.,Zhang, J.,Tan, D.,Wakimoto, H.,Cahill, D.P.,Bai, X.,Luo, X.,Asara, J.M.,Subramaniam, S.,Shan, Y.,Wu, X.
Autopalmitoylation of IDH1-R132H regulates its neomorphic activity in cancer cells.
Nat.Chem.Biol., 2026

PubMed 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 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.

PubMed: 41530531
DOI: 10.1038/s41589-025-02131-8

Experimental method

ELECTRON MICROSCOPY (2.85 Å)