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Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design

Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design
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 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.

Journal Article
0092-8674
1045-1058.e16
Dong, Yin Yao
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Wang, Hua
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Cochrane, Stephen A.
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Hamedzadeh, Sadra
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Wyszyński, Filip J.
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Bushell, Simon R.
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Widdick, David A.
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Sajid, Andaleeb
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Liu, Wei-Min
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Lee, Seung Seo
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Minall, Leanne
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Mehmood, Shahid
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Strain-Damerell, Claire
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Chalk, Rod
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Burgess-Brown, Nicola A
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Bibb, Mervyn J
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Barry Iii, Clifton E
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Davis, Benjamin G
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Dong, Yin Yao
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Wang, Hua
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Pike, Ashley C.W.
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Bushell, Simon R.
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Liu, Wei-Min
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Lee, Seung Seo
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Machida, Takuya
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Minall, Leanne
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Mehmood, Shahid
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Chu, Amy
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Shrestha, Leela
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Mukhopadhyay, Shubhashish M M
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Strain-Damerell, Claire
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Chalk, Rod
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Barry Iii, Clifton E
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Robinson, Carol V
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Davis, Benjamin G
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Carpenter, Elisabeth P
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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 and Carpenter, Elisabeth P (2018) Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design. Cell, 175 (4), 1045-1058.e16. (doi:10.1016/j.cell.2018.10.037).

Record type: Article

Abstract

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.

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CELL D 18-00775R2 DPAGT1 structure Cell Combined YD v2 - Accepted Manuscript
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1-s2.0-S009286741831393X-main (1) - Version of Record
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More information

Accepted/In Press date: 18 October 2018
e-pub ahead of print date: 1 November 2018
Published date: 1 November 2018
Keywords: Journal Article

Identifiers

Local EPrints ID: 426086
URI: http://eprints.soton.ac.uk/id/eprint/426086
ISSN: 0092-8674
PURE UUID: e6b20f4d-833e-4886-978f-70b0c30e1346
ORCID for Seung Seo Lee: ORCID iD orcid.org/0000-0002-8598-3303

Catalogue record

Date deposited: 13 Nov 2018 17:30
Last modified: 26 Nov 2021 07:09

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Contributors

Author: Yin Yao Dong
Author: Hua Wang
Author: Ashley C.W. Pike
Author: Stephen A. Cochrane
Author: Sadra Hamedzadeh
Author: Filip J. Wyszyński
Author: Simon R. Bushell
Author: Sylvain F. Royer
Author: David A. Widdick
Author: Andaleeb Sajid
Author: Helena I. Boshoff
Author: Yumi Park
Author: Ricardo Lucas
Author: Wei-Min Liu
Author: Seung Seo Lee ORCID iD
Author: Takuya Machida
Author: Leanne Minall
Author: Shahid Mehmood
Author: Katsiaryna Belaya
Author: Wei-Wei Liu
Author: Amy Chu
Author: Leela Shrestha
Author: Shubhashish M M Mukhopadhyay
Author: Claire Strain-Damerell
Author: Rod Chalk
Author: Nicola A Burgess-Brown
Author: Mervyn J Bibb
Author: Clifton E Barry Iii
Author: Carol V Robinson
Author: David Beeson
Author: Benjamin G Davis
Author: Elisabeth P Carpenter

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