Cargando…

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

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, GPT) catalyzes the...

Descripción completa

Detalles Bibliográficos
Autores principales: Yoo, Jiho, Mashalidis, Ellene H., Kuk, Alvin C. Y., Yamamoto, Kazuki, Kaeser, Benjamin, Ichikawa, Satoshi, Lee, Seok-Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840018/
https://www.ncbi.nlm.nih.gov/pubmed/29459785
http://dx.doi.org/10.1038/s41594-018-0031-y
_version_ 1783304495511371776
author Yoo, Jiho
Mashalidis, Ellene H.
Kuk, Alvin C. Y.
Yamamoto, Kazuki
Kaeser, Benjamin
Ichikawa, Satoshi
Lee, Seok-Yong
author_facet Yoo, Jiho
Mashalidis, Ellene H.
Kuk, Alvin C. Y.
Yamamoto, Kazuki
Kaeser, Benjamin
Ichikawa, Satoshi
Lee, Seok-Yong
author_sort Yoo, Jiho
collection PubMed
description 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, 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 by 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. Our 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 for the design of MraY-specific inhibitors as potential antibiotics.
format Online
Article
Text
id pubmed-5840018
institution National Center for Biotechnology Information
language English
publishDate 2018
record_format MEDLINE/PubMed
spelling pubmed-58400182018-08-19 GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation Yoo, Jiho Mashalidis, Ellene H. Kuk, Alvin C. Y. Yamamoto, Kazuki Kaeser, Benjamin Ichikawa, Satoshi Lee, Seok-Yong Nat Struct Mol Biol Article 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, 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 by 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. Our 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 for the design of MraY-specific inhibitors as potential antibiotics. 2018-02-19 2018-03 /pmc/articles/PMC5840018/ /pubmed/29459785 http://dx.doi.org/10.1038/s41594-018-0031-y Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Yoo, Jiho
Mashalidis, Ellene H.
Kuk, Alvin C. Y.
Yamamoto, Kazuki
Kaeser, Benjamin
Ichikawa, Satoshi
Lee, Seok-Yong
GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation
title GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation
title_full GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation
title_fullStr GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation
title_full_unstemmed GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation
title_short GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation
title_sort glcnac-1-p-transferase-tunicamycin complex structure reveals basis for inhibition of n-glycosylation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840018/
https://www.ncbi.nlm.nih.gov/pubmed/29459785
http://dx.doi.org/10.1038/s41594-018-0031-y
work_keys_str_mv AT yoojiho glcnac1ptransferasetunicamycincomplexstructurerevealsbasisforinhibitionofnglycosylation
AT mashalidiselleneh glcnac1ptransferasetunicamycincomplexstructurerevealsbasisforinhibitionofnglycosylation
AT kukalvincy glcnac1ptransferasetunicamycincomplexstructurerevealsbasisforinhibitionofnglycosylation
AT yamamotokazuki glcnac1ptransferasetunicamycincomplexstructurerevealsbasisforinhibitionofnglycosylation
AT kaeserbenjamin glcnac1ptransferasetunicamycincomplexstructurerevealsbasisforinhibitionofnglycosylation
AT ichikawasatoshi glcnac1ptransferasetunicamycincomplexstructurerevealsbasisforinhibitionofnglycosylation
AT leeseokyong glcnac1ptransferasetunicamycincomplexstructurerevealsbasisforinhibitionofnglycosylation