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GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation.

Publication ,  Journal Article
Yoo, J; Mashalidis, EH; Kuk, ACY; Yamamoto, K; Kaeser, B; Ichikawa, S; Lee, S-Y
Published in: Nat Struct Mol Biol
March 2018

N-linked glycosylation is a predominant post-translational modification of protein in eukaryotes, and its dysregulation is the etiology of several human disorders. The enzyme UDP-N-acetylglucosamine:dolichyl-phosphate N-acetylglucosaminephosphotransferase (GlcNAc-1-P-transferase or GPT) catalyzes the first and committed step of N-linked glycosylation in the endoplasmic reticulum membrane, and it is the target of the natural product tunicamycin. Tunicamycin has potent antibacterial activity, inhibiting the bacterial cell wall synthesis enzyme MraY, but its usefulness as an antibiotic is limited by off-target inhibition of human GPT. Our understanding of how tunicamycin inhibits N-linked glycosylation and efforts to selectively target MraY are hampered by a lack of structural information. Here we present crystal structures of human GPT in complex with tunicamycin. Structural and functional analyses reveal the difference between GPT and MraY in their mechanisms of inhibition by tunicamycin. We demonstrate that this difference could be exploited to design MraY-specific inhibitors as potential antibiotics.

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Published In

Nat Struct Mol Biol

DOI

EISSN

1545-9985

Publication Date

March 2018

Volume

25

Issue

3

Start / End Page

217 / 224

Location

United States

Related Subject Headings

  • Tunicamycin
  • Transferases (Other Substituted Phosphate Groups)
  • Transferases
  • Substrate Specificity
  • Protein Multimerization
  • Protein Binding
  • Models, Molecular
  • Magnesium
  • Humans
  • Glycosylation
 

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Yoo, J., Mashalidis, E. H., Kuk, A. C. Y., Yamamoto, K., Kaeser, B., Ichikawa, S., & Lee, S.-Y. (2018). GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation. Nat Struct Mol Biol, 25(3), 217–224. https://doi.org/10.1038/s41594-018-0031-y
Yoo, Jiho, Ellene H. Mashalidis, Alvin C. Y. Kuk, Kazuki Yamamoto, Benjamin Kaeser, Satoshi Ichikawa, and Seok-Yong Lee. “GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation.Nat Struct Mol Biol 25, no. 3 (March 2018): 217–24. https://doi.org/10.1038/s41594-018-0031-y.
Yoo J, Mashalidis EH, Kuk ACY, Yamamoto K, Kaeser B, Ichikawa S, et al. GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation. Nat Struct Mol Biol. 2018 Mar;25(3):217–24.
Yoo, Jiho, et al. “GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation.Nat Struct Mol Biol, vol. 25, no. 3, Mar. 2018, pp. 217–24. Pubmed, doi:10.1038/s41594-018-0031-y.
Yoo J, Mashalidis EH, Kuk ACY, Yamamoto K, Kaeser B, Ichikawa S, Lee S-Y. GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation. Nat Struct Mol Biol. 2018 Mar;25(3):217–224.

Published In

Nat Struct Mol Biol

DOI

EISSN

1545-9985

Publication Date

March 2018

Volume

25

Issue

3

Start / End Page

217 / 224

Location

United States

Related Subject Headings

  • Tunicamycin
  • Transferases (Other Substituted Phosphate Groups)
  • Transferases
  • Substrate Specificity
  • Protein Multimerization
  • Protein Binding
  • Models, Molecular
  • Magnesium
  • Humans
  • Glycosylation