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Structural basis of the pleiotropic and specific phenotypic consequences of missense mutations in the multifunctional NAD(P)H:quinone oxidoreductase 1 and their pharmacological rescue

Redox Biol. 2021-08; 
Juan Luis Pacheco-Garcia, Ernesto Anoz-Carbonell, Pavla Vankova, Adithi Kannan, Rogelio Palomino-Morales, Noel Mesa-Torres, Eduardo Salido, Petr Man, Milagros Medina, Athi N Naganathan, Angel L Pey
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Mutagenesis Services The mutations P187S and S82D were introduced by site-directed mutagenesis on the wild-type (WT) NQO1 cDNA cloned into the pCINEO plasmid by GenScript (Leiden, The Netherlands). Get A Quote

摘要

The multifunctional nature of human flavoproteins is critically linked to their ability to populate multiple conformational states. Ligand binding, post-translational modifications and disease-associated mutations can reshape this functional landscape, although the structure-function relationships of these effects are not well understood. Herein, we characterized the structural and functional consequences of two mutations (the cancer-associated P187S and the phosphomimetic S82D) on different ligation states which are relevant to flavin binding, intracellular stability and catalysis of the disease-associated NQO1 flavoprotein. We found that these mutations affected the stability locally and their effects propaga... More

关键词

Disease-causing mutation, Flavoprotein, Ligand binding, Multifunctional protein, NQO1, Post-translational modification