Abstract
UDP-glucuronosyltransferases are the principal enzymes involved in the glucuronidation of metabolites and xenobiotics for physiological clearance in humans. Though glucuronidation is an indispensable process in the phase II metabolic pathway, UGT-mediated glucuronidation of most prescribed drugs (> 55%) and clinical evidence of UGT-associated drug resistance are major concerns for therapeutic development. While UGTs are highly conserved enzymes, they manifest unique substrate and inhibitor specificity which is poorly understood given the dearth of experimentally determined full-length structures. Such information is important not only to conceptualize their specificity but is central to the design of inhibitors specific to a given UGT in order to avoid toxicity associated with pan-UGT inhibitors. Here, we provide the 1H, 13C and 15N backbone (~ 90%) and sidechain (~ 62%) assignments for the C-terminal domain of UGT2B17, which can be used to determine the molecular binding sites of inhibitor and substrate, and to understand the atomic basis for inhibitor selectivity between UGT2B17 and other members of the UGT2B subfamily. Given the physiological relevance of UGT2B17 in the elimination of hormone-based cancer drugs, these assignments will contribute towards dissecting the structural basis for substrate specificity, selective inhibitor recognition and other aspects of enzyme activity with the goal of selectively overcoming glucuronidation-based drug resistance.
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Data availability
NMR resonance assignments have been deposited to the BMRB under the accession code: 51,683.
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Acknowledgements
We thank Chantal Guillemette for the kind gift of the UGT2B17 plasmid. This work was supported by NIH RO1CA98571 & RO1CA80728 and the Institute for Research in Immunology and Cancer Center of Excellence in Commercialization (IRICoR). KLBB holds a Canada Research Chair in Molecular Biology of the Cell Nucleus.
Funding
This work was supported by NIH RO1CA98571 & RO1CA80728 and the Institute for Research in Immunology and Cancer Center of Excellence in Commercialization (IRICoR).
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JG and MO: produced the recombinant protein. MO: performed the NMR acquisition and spectral processing. AS: did the spectral analyses and chemical shift assignments, wrote the main manuscript text and prepared all figures. KB: contributed to project conceptualization, analysis and manuscript editing. All authors reviewed the manuscript.
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Sulekha, A., Osborne, M.J., Gasiorek, J. et al. 1H, 13C, 15N Backbone and sidechain chemical shift assignments of the C-terminal domain of human UDP-glucuronosyltransferase 2B17 (UGT2B17-C). Biomol NMR Assign 17, 67–73 (2023). https://doi.org/10.1007/s12104-023-10122-w
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DOI: https://doi.org/10.1007/s12104-023-10122-w