14CT

Structure of liver pyruvate kinase in complex with allosteric activator 8f

Summary for 14CT

• Entry DOI: 10.2210/pdb14ct/pdb
• Group deposition: Z-shaped allosteric ligands as activators of liver pyruvate kinase (G_1002372)
• Descriptor: Isoform L-type of Pyruvate kinase PKLR, 1,6-di-O-phosphono-beta-D-fructofuranose, OXALATE ION, ... (7 entities in total)
• Functional Keywords: pyruvate kinase, fluorescence, allosteric site, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 392113.19

Authors

Lulla, A.,Rodriguez Rivero, A.,Grotli, M.,Hyvonen, M. (deposition date: 2026-04-28, release date: 2026-10-14, Last modification date: 2026-11-04)

Primary citation

Monjas, L.,Rodriguez Rivero, A.,Fuchtbauer, A.F.,Nilsson, O.,Haversen, L.,Lulla, A.,Brear, P.,Rutberg, M.,Bergh, P.O.,Boren, J.,Mardinoglu, A.,Hyvonen, M.,Grotli, M.
Symmetry-guided fusion converts weak liver pyruvate kinase inhibitors into potent allosteric activators.
Rsc Med Chem, 2026

PubMed Abstract: Structure-guided exploitation of symmetry within multimeric protein interfaces offers an opportunity to convert partial ligand-binding poses into higher-affinity modulators. Here, we report a class of symmetrical "Z-shaped" allosteric activators of human liver pyruvate kinase (PKL), generated by symmetry-guided fusion of binding poses identified in inhibitor-bound crystal structures. The resulting ligands span the inter-subunit pocket at the tetrameric dimer-dimer interface and display substantially enhanced activity, with several analogues showing nanomolar activation potency. In HepG2 PKM2-knockout cells, the compounds increased PKL activity, maximal mitochondrial respiratory capacity and glycolytic proton efflux without altering PKL expression, Ser113 phosphorylation-dependent localisation, cell proliferation or triglyceride accumulation under the conditions examined. These findings establish symmetry-guided ligand fusion as a productive design strategy in this PKL system and provide structurally defined chemical tools for investigating the metabolic consequences of direct PKL activation.

PubMed: 42877870
DOI: 10.1039/d6md00604c

Experimental method

X-RAY DIFFRACTION (2.484 Å)