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Defining the structural origin of the substrate sequence independence of o-glcnacase using a combination of molecular docking and dynamics simulation
Martin, Joanne C; Fadda, Elisa; Ito, Keigo; Woods, Robert J
Protein glycosylation with O-linked N-acetylglucosamine (O-GlcNAc) is a post-translational modification of serine/threonine residues in nucleocytoplasmic proteins. O-GlcNAc has been shown to play a role in many different cellular processes and O-GlcNAcylation is often found at sites that are also known to be phosphorylated. Unlike phosphorylation, O-GlcNAc levels are regulated by only two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (O-GlcNAcase or OGA). So far, no obvious consensus sequence has been found for sites of O-GlcNAcylation. Additionally, O-GlcNAcase recognizes and cleaves all O-GlcNAcylated proteins, independent of their sequence. In this work, we generate and analyze five models of O-GlcNAcylated peptides in complex with a bacterial OGA. Each of the five glycopeptides bind to OGA in a similar fashion, with OGA-peptide interactions primarily, but not exclusively, involving the peptide backbone atoms, thus explaining the lack of sensitivity to peptide sequence. Nonetheless, differences in peptide sequences, particularly at the -1 to -4 positions, lead to variations in predicted affinity, consistent with observed experimental variations in enzyme kinetics. The potential exists, therefore, to employ the present analysis to guide the development glycopeptide-specific inhibitors, or conversely, the conversion of OGA into a reagent that could target specific O-GlcNAcylated peptide sequences.
Keyword(s): beta-n-acetylglucosaminidase (o-glcnacase); glycam; molecular dynamics; o-linked n-acetyl-glucosamine (o-glcnac); protein glycosylation; linked n-acetylglucosamine; mutational hot-spot; nucleocytoplasmic proteins; kinetic-analysis; force-field; c-myc; phosphorylation; inhibition; mechanism; beta
Publication Date:
Type: Journal article
Peer-Reviewed: Unknown
Institution: NUI Galway
Publisher(s): Oxford University Press (OUP)
First Indexed: 2019-03-23 06:27:03 Last Updated: 2019-03-23 06:27:03