Abstract
O-GlcNAc hydrolase (OGA) catalyzes removal of βα-linked N-acetyl-D-glucosamine from serine and threonine residues. We report crystal structures of Homo sapiens OGA catalytic domain in apo and inhibited states, revealing a flexible dimer that displays three unique conformations and is characterized by subdomain α-helix swapping. These results identify new structural features of the substrate-binding groove adjacent to the catalytic site and open new opportunities for structural, mechanistic and drug discovery activities.
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Acknowledgements
We thank J. Duffy, J. Schachter, J. Marcus, H. Su, B. Hayes, K. Babaoglu, D. Vocadlo, E. McEachern and G. McGaughey for valuable discussions, and M.R. Heo for performing size-exclusion chromatography and dynamic light scattering analysis. X-ray diffraction data were collected at beamline 17-ID in the facilities of the Industrial Macromolecular Crystallography Association Collaborative Access Team (IMCA-CAT) at the Advanced Photon Source, Argonne National Laboratories. Use of the IMCA-CAT beamline was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute. Use of the Advance Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357.
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D.J.K., N.L.E., K.J.L. and S.M.S. designed the project; D.J.K., N.L.E., S.B.P., J.R., R.E.F., D.L.H., J.M.S., H.K. and M.K. performed experiments; D.J.K., N.L.E., K.J.L., S.S., S.M.S., F.H. and H.S. interpreted experimental results; D.J.K., K.J.L. and N.L.E. prepared the manuscript.
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The authors are current or former employees of Merck & Co., Inc. USA and potentially own stock and/or hold stock options in the Company.
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Elsen, N., Patel, S., Ford, R. et al. Insights into activity and inhibition from the crystal structure of human O-GlcNAcase. Nat Chem Biol 13, 613–615 (2017). https://doi.org/10.1038/nchembio.2357
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DOI: https://doi.org/10.1038/nchembio.2357
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