7lw1
Human phosphofructokinase-1 liver type bound to activator NA-11Human phosphofructokinase-1 liver type bound to activator NA-11
Structural highlights
Publication Abstract from PubMedIn neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading pathogens. However, excessive NOX2 activity can exacerbate inflammation, as in acute respiratory distress syndrome (ARDS). Here, we use two unbiased chemical proteomic strategies to show that small-molecule LDC7559, or a more potent designed analog NA-11, inhibits the NOX2-dependent oxidative burst in neutrophils by activating the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) and dampening flux through the pentose phosphate pathway. Accordingly, neutrophils treated with NA-11 had reduced NOX2-dependent outputs, including neutrophil cell death (NETosis) and tissue damage. A high-resolution structure of PFKL confirmed binding of NA-11 to the AMP/ADP allosteric activation site and explained why NA-11 failed to agonize phosphofructokinase-1 platelet type (PFKP) or muscle type (PFKM). Thus, NA-11 represents a tool for selective activation of PFKL, the main phosphofructokinase-1 isoform expressed in immune cells. Selective activation of PFKL suppresses the phagocytic oxidative burst.,Amara N, Cooper MP, Voronkova MA, Webb BA, Lynch EM, Kollman JM, Ma T, Yu K, Lai Z, Sangaraju D, Kayagaki N, Newton K, Bogyo M, Staben ST, Dixit VM Cell. 2021 Aug 19;184(17):4480-4494.e15. doi: 10.1016/j.cell.2021.07.004. Epub, 2021 Jul 27. PMID:34320407[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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