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Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design
Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glyco...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218659/ https://www.ncbi.nlm.nih.gov/pubmed/30388443 http://dx.doi.org/10.1016/j.cell.2018.10.037 |
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author | Dong, Yin Yao Wang, Hua Pike, Ashley C.W. Cochrane, Stephen A. Hamedzadeh, Sadra Wyszyński, Filip J. Bushell, Simon R. Royer, Sylvain F. Widdick, David A. Sajid, Andaleeb Boshoff, Helena I. Park, Yumi Lucas, Ricardo Liu, Wei-Min Lee, Seung Seo Machida, Takuya Minall, Leanne Mehmood, Shahid Belaya, Katsiaryna Liu, Wei-Wei Chu, Amy Shrestha, Leela Mukhopadhyay, Shubhashish M.M. Strain-Damerell, Claire Chalk, Rod Burgess-Brown, Nicola A. Bibb, Mervyn J. Barry III, Clifton E. Robinson, Carol V. Beeson, David Davis, Benjamin G. Carpenter, Elisabeth P. |
author_facet | Dong, Yin Yao Wang, Hua Pike, Ashley C.W. Cochrane, Stephen A. Hamedzadeh, Sadra Wyszyński, Filip J. Bushell, Simon R. Royer, Sylvain F. Widdick, David A. Sajid, Andaleeb Boshoff, Helena I. Park, Yumi Lucas, Ricardo Liu, Wei-Min Lee, Seung Seo Machida, Takuya Minall, Leanne Mehmood, Shahid Belaya, Katsiaryna Liu, Wei-Wei Chu, Amy Shrestha, Leela Mukhopadhyay, Shubhashish M.M. Strain-Damerell, Claire Chalk, Rod Burgess-Brown, Nicola A. Bibb, Mervyn J. Barry III, Clifton E. Robinson, Carol V. Beeson, David Davis, Benjamin G. Carpenter, Elisabeth P. |
author_sort | Dong, Yin Yao |
collection | PubMed |
description | Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic “lipid-altered” tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug. |
format | Online Article Text |
id | pubmed-6218659 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-62186592018-11-09 Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design Dong, Yin Yao Wang, Hua Pike, Ashley C.W. Cochrane, Stephen A. Hamedzadeh, Sadra Wyszyński, Filip J. Bushell, Simon R. Royer, Sylvain F. Widdick, David A. Sajid, Andaleeb Boshoff, Helena I. Park, Yumi Lucas, Ricardo Liu, Wei-Min Lee, Seung Seo Machida, Takuya Minall, Leanne Mehmood, Shahid Belaya, Katsiaryna Liu, Wei-Wei Chu, Amy Shrestha, Leela Mukhopadhyay, Shubhashish M.M. Strain-Damerell, Claire Chalk, Rod Burgess-Brown, Nicola A. Bibb, Mervyn J. Barry III, Clifton E. Robinson, Carol V. Beeson, David Davis, Benjamin G. Carpenter, Elisabeth P. Cell Article Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic “lipid-altered” tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug. Cell Press 2018-11-01 /pmc/articles/PMC6218659/ /pubmed/30388443 http://dx.doi.org/10.1016/j.cell.2018.10.037 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Dong, Yin Yao Wang, Hua Pike, Ashley C.W. Cochrane, Stephen A. Hamedzadeh, Sadra Wyszyński, Filip J. Bushell, Simon R. Royer, Sylvain F. Widdick, David A. Sajid, Andaleeb Boshoff, Helena I. Park, Yumi Lucas, Ricardo Liu, Wei-Min Lee, Seung Seo Machida, Takuya Minall, Leanne Mehmood, Shahid Belaya, Katsiaryna Liu, Wei-Wei Chu, Amy Shrestha, Leela Mukhopadhyay, Shubhashish M.M. Strain-Damerell, Claire Chalk, Rod Burgess-Brown, Nicola A. Bibb, Mervyn J. Barry III, Clifton E. Robinson, Carol V. Beeson, David Davis, Benjamin G. Carpenter, Elisabeth P. Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design |
title | Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design |
title_full | Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design |
title_fullStr | Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design |
title_full_unstemmed | Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design |
title_short | Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design |
title_sort | structures of dpagt1 explain glycosylation disease mechanisms and advance tb antibiotic design |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218659/ https://www.ncbi.nlm.nih.gov/pubmed/30388443 http://dx.doi.org/10.1016/j.cell.2018.10.037 |
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