Our paper “Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation” has been released: eLife e45068. This work is a tour de force of PKM2 (pyruvate kinase M2) biophysics (kudos to the lead author Jamie Macpherson), yielding several strong conclusions about the physiological role of its allosteric ligands.
- The allosteric ligand fructose-1,6-bipphosphate (FBP) is a strong binder and its cellular concentration is high enough to saturate PKM2 binding sites. It also means that FBP is not an allosteric regulator under normal physological conditions. However, it strongly promotes tetramerisation and a concommitant increase in enzymatic activity.
- Amino acids, which bind to a distinct pocket, are allosteric modulators of PKM2. Using Phe as an examplary allosteric inhibitor, molecular simulations and analysis with our AlloHubMat software highlighted allosteric hub residues.
- Mutation of allosteric hub residues showed clear abrogation or modulation of Phe’s allosteric effects. Additionally, cross-talk between the allosteric pathways of FBP and Phe was detected.