5X0I
Crystal structure of PKM2 R399E mutant complexed with FBP and serine
Summary for 5X0I
| Entry DOI | 10.2210/pdb5x0i/pdb |
| Descriptor | Pyruvate kinase PKM, 1,6-di-O-phosphono-beta-D-fructofuranose, SERINE, ... (7 entities in total) |
| Functional Keywords | pyruvate kinase, glycolysis, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 243027.35 |
| Authors | Wang, W.C.,Chen, T.J. (deposition date: 2017-01-20, release date: 2018-01-31, Last modification date: 2023-11-22) |
| Primary citation | Chen, T.J.,Wang, H.J.,Liu, J.S.,Cheng, H.H.,Hsu, S.C.,Wu, M.C.,Lu, C.H.,Wu, Y.F.,Wu, J.W.,Liu, Y.Y.,Kung, H.J.,Wang, W.C. Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation. Commun Biol, 2:105-105, 2019 Cited by PubMed Abstract: PKM2 is a key metabolic enzyme central to glucose metabolism and energy expenditure. Multiple stimuli regulate PKM2's activity through allosteric modulation and post-translational modifications. Furthermore, PKM2 can partner with KDM8, an oncogenic demethylase and enter the nucleus to serve as a HIF1α co-activator. Yet, the mechanistic basis of the exon-10 region in allosteric regulation and nuclear translocation remains unclear. Here, we determined the crystal structures and kinetic coupling constants of exon-10 tumor-related mutants (H391Y and R399E), showing altered structural plasticity and reduced allostery. Immunoprecipitation analysis revealed increased interaction with KDM8 for H391Y, R399E, and G415R. We also found a higher degree of HIF1α-mediated transactivation activity, particularly in the presence of KDM8. Furthermore, overexpression of PKM2 mutants significantly elevated cell growth and migration. Together, PKM2 exon-10 mutations lead to structure-allostery alterations and increased nuclear functions mediated by KDM8 in breast cancer cells. Targeting the PKM2-KDM8 complex may provide a potential therapeutic intervention. PubMed: 30911680DOI: 10.1038/s42003-019-0343-4 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.64 Å) |
Structure validation
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