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Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design

138 Pages Posted: 7 Jun 2018 Sneak Peek Status: Published

See all articles by Yin Yao Dong

Yin Yao Dong

University of Oxford - Structural Genomics Consortium (SGC)

Hua Wang

University of Oxford - Chemistry Research Laboratory

Ashley C. W. Pike

University of Oxford - Structural Genomics Consortium (SGC)

Stephen A. Cochrane

University of Oxford - Chemistry Research Laboratory; Queen's University Belfast - School of Chemistry and Chemical Engineering

Sadra Hamedzadeh

University of Oxford - Chemistry Research Laboratory

Filip J. Wyszyński

University of Oxford - Chemistry Research Laboratory

Simon R. Bushell

University of Oxford - Structural Genomics Consortium (SGC)

Sylvain F. Royer

University of Oxford - Chemistry Research Laboratory

David A. Widdick

John Innes Centre - Department of Molecular Microbiology

Andaleeb Sajid

Government of the United States of America - Tuberculosis Research Section

Helena I. Boshoff

Government of the United States of America - Tuberculosis Research Section

Ricardo Lucas

University of Oxford - Chemistry Research Laboratory

Wei-Min Liu

University of Oxford - Chemistry Research Laboratory

Seung Seo Lee

University of Oxford - Chemistry Research Laboratory

Takuya Machida

University of Oxford - Chemistry Research Laboratory

Shahid Mehmood

University of Oxford - Department of Chemistry

Katsiaryna Belaya

University of Oxford - Nuffield Department of Clinical Neurosciences

Wei-Wei Liu

University of Oxford - Nuffield Department of Clinical Neurosciences

Amy Chu

University of Oxford - Structural Genomics Consortium (SGC)

Leela Shrestha

University of Oxford - Structural Genomics Consortium (SGC)

Shubhashish M. M. Mukhopadhyay

University of Oxford - Structural Genomics Consortium (SGC)

Nicola A. Burgess-Brown

University of Oxford - Structural Genomics Consortium (SGC)

Mervyn J. Bibb

John Innes Centre - Department of Molecular Microbiology

Clifton E. Barry III

Government of the United States of America - Tuberculosis Research Section

Carol V. Robinson

University of Oxford - Department of Chemistry

David Beeson

University of Oxford - Nuffield Department of Clinical Neurosciences

Benjamin G. Davis

University of Oxford - Chemistry Research Laboratory

Elisabeth P. Carpenter

University of Oxford - Structural Genomics Consortium (SGC)

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Abstract

Protein glycosylation is a widespread post-translational modification. The first committed step to the lipid-linked glycan used for 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 congenital 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 as antibiotics. However, little is known about the mechanism or the effects of disease-associated mutations in this essential enzyme. 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 (and thus cause disease) and allow design of non-toxic ‘lipid-altered’ tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo thereby providing a promising new class of antimicrobial drug.

Suggested Citation

Dong, Yin Yao and Wang, Hua and Pike, Ashley C. W. and Cochrane, Stephen A. and Hamedzadeh, Sadra and Wyszyński, Filip J. and Bushell, Simon R. and Royer, Sylvain F. and Widdick, David A. and Sajid, Andaleeb and Boshoff, Helena I. and Lucas, Ricardo and Liu, Wei-Min and Lee, Seung Seo and Machida, Takuya and Mehmood, Shahid and Belaya, Katsiaryna and Liu, Wei-Wei and Chu, Amy and Shrestha, Leela and Mukhopadhyay, Shubhashish M. M. and Burgess-Brown, Nicola A. and Bibb, Mervyn J. and Barry III, Clifton E. and Robinson, Carol V. and Beeson, David and Davis, Benjamin G. and Carpenter, Elisabeth P., Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design (2018). Available at SSRN: https://ssrn.com/abstract=3188395 or http://dx.doi.org/10.2139/ssrn.3188395
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Yin Yao Dong

University of Oxford - Structural Genomics Consortium (SGC)

Roosevelt Drive
Old Road Campus Research Building
Oxford, England OX3 7DQ
United Kingdom

Hua Wang

University of Oxford - Chemistry Research Laboratory

12 Mansfield Road
Oxford, OX1 3TA
United Kingdom

Ashley C. W. Pike

University of Oxford - Structural Genomics Consortium (SGC)

Roosevelt Drive
Old Road Campus Research Building
Oxford, England OX3 7DQ
United Kingdom

Stephen A. Cochrane

University of Oxford - Chemistry Research Laboratory

12 Mansfield Road
Oxford, OX1 3TA
United Kingdom

Queen's University Belfast - School of Chemistry and Chemical Engineering

39 Stranmillis Road
David Keir Building
Belfast, BT9 5AG
United Kingdom

Sadra Hamedzadeh

University of Oxford - Chemistry Research Laboratory

12 Mansfield Road
Oxford, OX1 3TA
United Kingdom

Filip J. Wyszyński

University of Oxford - Chemistry Research Laboratory

12 Mansfield Road
Oxford, OX1 3TA
United Kingdom

Simon R. Bushell

University of Oxford - Structural Genomics Consortium (SGC)

Roosevelt Drive
Old Road Campus Research Building
Oxford, England OX3 7DQ
United Kingdom

Sylvain F. Royer

University of Oxford - Chemistry Research Laboratory

12 Mansfield Road
Oxford, OX1 3TA
United Kingdom

David A. Widdick

John Innes Centre - Department of Molecular Microbiology

Norwich, NR4 7UH
United Kingdom

Andaleeb Sajid

Government of the United States of America - Tuberculosis Research Section

Bethesda, MD 20892
United States

Helena I. Boshoff

Government of the United States of America - Tuberculosis Research Section

Bethesda, MD 20892
United States

Ricardo Lucas

University of Oxford - Chemistry Research Laboratory

12 Mansfield Road
Oxford, OX1 3TA
United Kingdom

Wei-Min Liu

University of Oxford - Chemistry Research Laboratory

12 Mansfield Road
Oxford, OX1 3TA
United Kingdom

Seung Seo Lee

University of Oxford - Chemistry Research Laboratory

12 Mansfield Road
Oxford, OX1 3TA
United Kingdom

Takuya Machida

University of Oxford - Chemistry Research Laboratory

12 Mansfield Road
Oxford, OX1 3TA
United Kingdom

Shahid Mehmood

University of Oxford - Department of Chemistry

Oxford, OX1 3QR
United Kingdom

Katsiaryna Belaya

University of Oxford - Nuffield Department of Clinical Neurosciences

Oxford
United Kingdom

Wei-Wei Liu

University of Oxford - Nuffield Department of Clinical Neurosciences

Oxford
United Kingdom

Amy Chu

University of Oxford - Structural Genomics Consortium (SGC)

Roosevelt Drive
Old Road Campus Research Building
Oxford, England OX3 7DQ
United Kingdom

Leela Shrestha

University of Oxford - Structural Genomics Consortium (SGC)

Roosevelt Drive
Old Road Campus Research Building
Oxford, England OX3 7DQ
United Kingdom

Shubhashish M. M. Mukhopadhyay

University of Oxford - Structural Genomics Consortium (SGC)

Roosevelt Drive
Old Road Campus Research Building
Oxford, England OX3 7DQ
United Kingdom

Nicola A. Burgess-Brown

University of Oxford - Structural Genomics Consortium (SGC)

Roosevelt Drive
Old Road Campus Research Building
Oxford, England OX3 7DQ
United Kingdom

Mervyn J. Bibb

John Innes Centre - Department of Molecular Microbiology

Norwich, NR4 7UH
United Kingdom

Clifton E. Barry III

Government of the United States of America - Tuberculosis Research Section

Bethesda, MD 20892
United States

Carol V. Robinson

University of Oxford - Department of Chemistry

Oxford, OX1 3QR
United Kingdom

David Beeson

University of Oxford - Nuffield Department of Clinical Neurosciences

Oxford
United Kingdom

Benjamin G. Davis

University of Oxford - Chemistry Research Laboratory ( email )

12 Mansfield Road
Oxford, OX1 3TA
United Kingdom

Elisabeth P. Carpenter (Contact Author)

University of Oxford - Structural Genomics Consortium (SGC) ( email )

Roosevelt Drive
Old Road Campus Research Building
Oxford, England OX3 7DQ
United Kingdom

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