Structural Confirmation of a Potential Cancer Therapeutic: Pyruvate Kinase Activator Restores Active Conformation to M2 Isoform

摘要

In summary each of the ligands in this study stabilized unique conformations of PKM2 HDX at the active site correlates with activation where reduced deuterium uptake at this region is seen for activated PKM2 and increased deuterium uptake is seen for inactivate PKM2 The HDX profile of the LDH pTyr shows one regions with reduced HDX which suggests a binding site for phosphor-tyrosine peptides Although FBP can only partially stabilize active conformations in the presence of pTyr, the DASA-58 activator can fully stabilize PKM2 conformations associated with the active state even in the presence of FBP and pTyr This work provides a structural mechanism to support the functional activation of PKM2 by allosteric activators