Motif-dependent binding on the intervening domain regulates O-GlcNAc transferase.

The modification of intracellular proteins with O-linked β-N-acetylglucosamine (O-GlcNAc) moieties is a highly dynamic process that spatiotemporally regulates nearly every important cellular program. Despite its significance, little is known about the substrate recognition and regulation modes of O-GlcNAc transferase (OGT), the primary enzyme responsible for O-GlcNAc addition. In this study, we identified the intervening domain (Int-D), a poorly understood protein fold found only in metazoan OGTs, as a specific regulator of OGT protein-protein interactions and substrate modification.

A novel binding site on the cryptic intervening domain is a motif-dependent regulator of O-GlcNAc transferase.

The modification of intracellular proteins with O-linked β- -acetylglucosamine (O-GlcNAc) moieties is a highly dynamic process that spatiotemporally regulates nearly every important cellular program. Despite its significance, little is known about the substrate recognition and regulation modes of O-GlcNAc transferase (OGT), the primary enzyme responsible for O-GlcNAc addition. In this study, we have identified the intervening domain (Int-D), a poorly understood protein fold found only in metazoan OGTs, as a specific regulator of OGT protein-protein interactions and substrate modification.

Molecular Interrogation to Crack the Case of O-GlcNAc.

The O-linked β-N-acetylglucosamine (O-GlcNAc) modification, termed O-GlcNAcylation, is an essential and dynamic post-translational modification in cells. O-GlcNAc transferase (OGT) installs this modification on serine and threonine residues, whereas O-GlcNAcase (OGA) hydrolyzes it. O-GlcNAc modifications are found on thousands of intracellular proteins involved in diverse biological processes.

Discovery of nicoyamycin A, an inhibitor of uropathogenic Escherichia coli growth in low iron environments.

High-throughput screening and activity-guided purification identified nicoyamycin A, a natural product comprised of an uncommon 3-methyl-1,4-dioxane ring incorporated into a desferrioxamine-like backbone via a spiroaminal linkage. Nicoyamycin A potently inhibits uropathogenic Escherichia coli growth in low iron medium, a promising step toward developing novel antibiotics to treat recalcitrant bacterial infections.