7CKK

Structural complex of FTO bound with Dac51

Summary for 7CKK

• Entry DOI: 10.2210/pdb7ckk/pdb
• Descriptor: Alpha-ketoglutarate-dependent dioxygenase FTO, N-OXALYLGLYCINE, 2-{[2,6-dichloro-4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]amino}-N-hydroxybenzamide, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, demethylase, rna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 54916.63

Authors

Yang, C.,Gan, J. (deposition date: 2020-07-17, release date: 2021-07-21, Last modification date: 2023-11-29)

Primary citation

Liu, Y.,Liang, G.,Xu, H.,Dong, W.,Dong, Z.,Qiu, Z.,Zhang, Z.,Li, F.,Huang, Y.,Li, Y.,Wu, J.,Yin, S.,Zhang, Y.,Guo, P.,Liu, J.,Xi, J.J.,Jiang, P.,Han, D.,Yang, C.G.,Xu, M.M.
Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance.
Cell Metab., 33:1221-1233.e11, 2021

PubMed Abstract: The ever-increasing understanding of the complexity of factors and regulatory layers that contribute to immune evasion facilitates the development of immunotherapies. However, the diversity of malignant tumors limits many known mechanisms in specific genetic and epigenetic contexts, manifesting the need to discover general driver genes. Here, we have identified the mA demethylase FTO as an essential epitranscriptomic regulator utilized by tumors to escape immune surveillance through regulation of glycolytic metabolism. We show that FTO-mediated mA demethylation in tumor cells elevates the transcription factors c-Jun, JunB, and C/EBPβ, which allows the rewiring of glycolytic metabolism. Fto knockdown impairs the glycolytic activity of tumor cells, which restores the function of CD8 T cells, thereby inhibiting tumor growth. Furthermore, we developed a small-molecule compound, Dac51, that can inhibit the activity of FTO, block FTO-mediated immune evasion, and synergize with checkpoint blockade for better tumor control, suggesting reprogramming RNA epitranscriptome as a potential strategy for immunotherapy.

PubMed: 33910046
DOI: 10.1016/j.cmet.2021.04.001

Experimental method

X-RAY DIFFRACTION (2.35 Å)