6nn4
The structure of human liver pyruvate kinase, hLPYK-D499N, in complex with Fru-1,6-BP
Structural highlights
DiseaseKPYR_HUMAN Defects in PKLR are the cause of pyruvate kinase hyperactivity (PKHYP) [MIM:102900; also known as high red cell ATP syndrome. This autosomal dominant phenotype is characterized by increase of red blood cell ATP.[1] Defects in PKLR are the cause of pyruvate kinase deficiency of red cells (PKRD) [MIM:266200. A frequent cause of hereditary non-spherocytic hemolytic anemia. Clinically, pyruvate kinase-deficient patients suffer from a highly variable degree of chronic hemolysis, ranging from severe neonatal jaundice and fatal anemia at birth, severe transfusion-dependent chronic hemolysis, moderate hemolysis with exacerbation during infection, to a fully compensated hemolysis without apparent anemia. FunctionKPYR_HUMAN Plays a key role in glycolysis (By similarity). Publication Abstract from PubMedHuman 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, Delta529/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-pi 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. Changes in the allosteric site of human liver pyruvate kinase upon activator binding include the breakage of an intersubunit cation-pi bond.,McFarlane JS, Ronnebaum TA, Meneely KM, Chilton A, Fenton AW, Lamb AL Acta Crystallogr F Struct Biol Commun. 2019 Jun 1;75(Pt 6):461-469. doi:, 10.1107/S2053230X19007209. Epub 2019 Jun 10. PMID:31204694[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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