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Structural and functional insight into human O-GlcNAcase

Abstract

O-GlcNAc hydrolase (OGA) removes O-linked N-acetylglucosamine (O-GlcNAc) from a myriad of nucleocytoplasmic proteins. Through co-expression and assembly of OGA fragments, we determined the three-dimensional structure of human OGA, revealing an unusual helix-exchanged dimer that lays a structural foundation for an improved understanding of substrate recognition and regulation of OGA. Structures of OGA in complex with a series of inhibitors define a precise blueprint for the design of inhibitors that have clinical value.

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Figure 1: Function and structure of hOGA.
Figure 2: Ligand binding to hOGA.

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Protein Data Bank

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Protein Data Bank

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Acknowledgements

The authors thank the Diamond Light Source for beamtime (proposals mx-1221, mx-7864, and mx-9948), and the staff of beamlines I02, I03, and I24 for assistance. The authors are grateful to. J.P. Turkenburg and S. Hart for their help in crystal testing and data collection. The authors thank J. Borgia, S. Grist, A. Leech, and L. Haigh for technical support. This research was supported by funding from the Biotechnology and Biological Sciences Research Council (BB/K003836/1) and the Canadian Institutes of Health Research (MOP-123341), Brain Canada, Genome British Columbia, and the Michael Smith Foundation for Health Research. L.I.W. is supported by the Netherlands Organization for Scientific Research (NWO) and the Banting Postdoctoral Fellowships program are also thanked for financial support. R.B. is supported by an MSFHR Career Investigator Award. D.J.V. is supported as a Tier I Canada Research Chair in Chemical Glycobiology. G.J.D. is supported by the Royal Society through a Ken Murray research professorship. S.C. was funded through an Alzheimer's Research UK PhD fellowship.

Author information

Authors and Affiliations

Authors

Contributions

C.R. designed truncated constructs and cloned, expressed, crystallized, and solved the structure of the protein. S.C. designed truncated constructs and cloned, expressed, purified, and crystallized protein. W.A.O. cloned, purified, and crystallized protein. G.R.H. designed experiments and cloned and purified protein. L.I.W. performed cell culture and western blot assays. D.T.K. performed the kinetic characterization. V.V. synthesized VV347. R.B. and D.J.V. designed the pyrrolidine inhibitors. G.J.D. designed cloning and structural experiments. D.J.V. designed biochemical and inhibition experiments. C.R., D.J.V., and G.J.D. wrote the manuscript with contributions from all authors.

Corresponding authors

Correspondence to David J Vocadlo or Gideon J Davies.

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Competing interests

D.J.V. is a co-founder of and holds equity in the company Alectos Therapeutics. D.J.V. serves as CSO and Chair of the Scientific Advisory Board of Alectos Therapeutics, of which G.J.D. is a member.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1 and 2 and Supplementary Figures 1–16 (PDF 2317 kb)

Supplementary Note

Supplementary Procedures (PDF 569 kb)

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Roth, C., Chan, S., Offen, W. et al. Structural and functional insight into human O-GlcNAcase. Nat Chem Biol 13, 610–612 (2017). https://doi.org/10.1038/nchembio.2358

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