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

• Yin Yao Dong ^[1] ; Hua Wang ^[2] ; Ashley C. W. Pike ^[1] ; Stephen A. Cochrane ^[1] ; Sadra Hamedzadeh ^[1] ; Filip J. Wyszyński ^[1] ; Simon R. Bushell ^[1] ; S. Royer ^[1] ; David A. Widdick ^[4] ; Andaleeb Sajid ^[3] ; Helena I. M. Boshoff ^[3] ; Yumi Park ^[3] ; Ricardo Lucas ^[1] ; Wei-Min Liu ^[1] ; Seung Seo Lee ^[1] ; T. Machida ^[1] ; Leanne Minall ^[1] ; Shahid Mehmood ^[1] ; Katsiaryna Belaya ^[1] ; Wei-Wei Liu ^[1] ; Amy Chu ^[1] ; Leela Shrestha ^[1] ; Shubhashish M.M. Mukhopadhyay ^[1] ; Claire Strain-Damerell ^[1] ; Rod Chalk ^[1] ; Nicola A. Burgess-Brown ^[1] ; Mervyn Bibb ^[2] ; Clifton E. Barry III ^[3] ; Carol V. Robinson ^[1] ; David Beeson ^[1] ; Benjamin G. Davis ^[1] ; Elisabeth P. Carpenter ^[1]
  1. [1] University of Oxford

     University of Oxford

     Oxford District, Reino Unido

     
  2. [2] Francis Crick Institute

     Francis Crick Institute

     Reino Unido

     
  3. [3] National Institutes of Health

     National Institutes of Health

     Estados Unidos

     
  4. [4] John Innes Centre

     John Innes Centre

     Norwich District, Reino Unido

     

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• Localización: Cell, ISSN 0092-8674, Vol. 175, Nº. 4, 2018, págs. 1045-1058
• Idioma: inglés
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  • 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.