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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
Identifiers
http://hdl.handle.net/10379/12661
 https://doi.org/10.13025/27034
Publication Date
2013-10-16
Keywords
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
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Citation
Martin, Joanne C; Fadda, Elisa; Ito, Keigo; Woods, Robert J (2013). Defining the structural origin of the substrate sequence independence of o-glcnacase using a combination of molecular docking and dynamics simulation. Glycobiology 24 (1), 85-96
Abstract
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.
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Publisher
Oxford University Press (OUP)
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Attribution-NonCommercial-NoDerivs 3.0 Ireland
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Externally hosted open access publications with University of Galway authors (2)