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Human liver pyruvate kinase (hLPYK) converts phosphoenolpyruvate to pyruvate in the final step of glycolysis. hLPYK is allosterically activated by fructose-1,6-bisphosphate (Fru-1,6-BP). The allosteric site, as defined by previous structural studies, is located in domain C between the phosphate-binding loop (residues 444–449) and the allosteric loop (residues 527–533). In this study, the X-ray crystal structures of four hLPYK variants were solved to make structural correlations with existing functional data. The variants are D499N, W527H, Δ529/S531G (called GGG here) and S531E. The results revealed a conformational toggle between the open and closed positions of the allosteric loop. In the absence of Fru-1,6-BP the open position is stabilized, in part, by a cation–π bond between Trp527 and Arg538′ (from an adjacent monomer). In the S531E variant glutamate binds in place of the 6′-phosphate of Fru-1,6-BP in the allosteric site, leading to partial allosteric activation. Finally, the structure of the D499N mutant does not provide structural evidence for the previously observed allosteric activation of the D499N variant.

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Portable Document Format (PDF) file https://doi.org/10.1107/S2053230X19007209/rr5174sup1.pdf
Supplementary Tables and Figures.

PDB references: human liver pyruvate kinase, D499N variant, 6nn4; W527H variant, 6nn5; Δ529/S531G variant, 6nn7; S531E variant, 6nn8


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