9iqq

From Proteopedia

Crystal structure of PKM2 in complex with a natural activator

Structural highlights

9iqq is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.7Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KPYM_HUMAN Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival.^[1] ^[2] ^[3]

Publication Abstract from PubMed

This study identifies glutathione (GSH) as an endogenous A-A type allosteric activator of pyruvate kinase M2 (PKM2), stabilizing it in its active tetrameric form through binding at the A-A interface. This PKM2-GSH interaction links GSH metabolism to ferroptosis regulation. Transcriptomic analyses across cancers demonstrate strong correlations between GSH, SLC7A11, PKM2, glycolysis, and ferroptosis pathways. By depleting GSH and activating PKM2, ferroptosis is enhanced in PKM2-dependent cancer models. This approach leads to significant changes in central carbon and lipid metabolism, disrupts mitochondrial function, and drives ferroptotic cell death. The combined treatment markedly suppresses tumor growth in a xenograft model. Elevated PKM2 and SLC7A11 expression levels correlate with poorer survival outcomes, indicating their potential as biomarkers for ferroptosis-based therapy. The findings demonstrate a dual role for GSH in cellular homeostasis and identify the PKM2-GSH-SLC7A11 axis as a therapeutic target for aggressive cancers.

GSH as an A-A Type Allosteric Activator of PKM2: Modulating Cancer Cell Homeostasis and Ferroptosis Susceptibility.,Chen TJ, Lo CJ, Wu MJ, Sit WY, Hsu HY, Huang YC, Lu CH, Chen YL, Fang WK, Yang SM, Chen PL, Haraguchi T, Hiraoka Y, Lin CY, Cheng ML, Yang MH, Kung HJ, Wang WC Adv Sci (Weinh). 2025 Nov 10:e19368. doi: 10.1002/advs.202519368. PMID:41215470^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Stetak A, Veress R, Ovadi J, Csermely P, Keri G, Ullrich A. Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death. Cancer Res. 2007 Feb 15;67(4):1602-8. PMID:17308100 doi:10.1158/0008-5472.CAN-06-2870
↑ Lee J, Kim HK, Han YM, Kim J. Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription. Int J Biochem Cell Biol. 2008;40(5):1043-54. doi: 10.1016/j.biocel.2007.11.009., Epub 2007 Nov 29. PMID:18191611 doi:10.1016/j.biocel.2007.11.009
↑ Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A, Semenza GL. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011 May 27;145(5):732-44. doi: 10.1016/j.cell.2011.03.054. PMID:21620138 doi:10.1016/j.cell.2011.03.054
↑ Chen TJ, Lo CJ, Wu MJ, Sit WY, Hsu HY, Huang YC, Lu CH, Chen YL, Fang WK, Yang SM, Chen PL, Haraguchi T, Hiraoka Y, Lin CY, Cheng ML, Yang MH, Kung HJ, Wang WC. GSH as an A-A Type Allosteric Activator of PKM2: Modulating Cancer Cell Homeostasis and Ferroptosis Susceptibility. Adv Sci (Weinh). 2025 Nov 10:e19368. PMID:41215470 doi:10.1002/advs.202519368