Nature Structural & Molecular Biology
- 13, 365 - 371 (2006)
Published online: 26 March 2006; | doi:10.1038/nsmb1079
Structure and mechanism of a bacterial  -glucosaminidase having O-GlcNAcase activityRebecca J Dennis1, Edward J Taylor1, Matthew S Macauley2, Keith A Stubbs2, Johan P Turkenburg1, Samuel J Hart1, Gary N Black3, David J Vocadlo2 & Gideon J Davies11
York Structural Biology Laboratory, Department of Chemistry, University of York, York Y010 5YW, UK. 2
Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada. 3
Biomolecular and Biomedical Research Centre, School of Applied Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, UK.
Correspondence should be addressed to David J Vocadlo dvocadlo@sfu.ca or Gideon J Davies davies@ysbl.york.ac.uk
O-GlcNAc is an abundant post-translational modification of serine and threonine residues of nucleocytoplasmic proteins. This modification, found only within higher eukaryotes, is a dynamic modification that is often reciprocal to phosphorylation. In a manner analogous to phosphatases, a glycoside hydrolase termed O-GlcNAcase cleaves O-GlcNAc from modified proteins. Enzymes with high sequence similarity to human O-GlcNAcase are also found in human pathogens and symbionts. We report the three-dimensional structure of O-GlcNAcase from the human gut symbiont Bacteroides thetaiotaomicron both in its native form and in complex with a mimic of the reaction intermediate. Mutagenesis and kinetics studies show that the bacterial enzyme, very similarly to its human counterpart, operates via an unusual 'substrate-assisted' catalytic mechanism, which will inform the rational design of enzyme inhibitors.
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