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Instruments / Technical Area	Publication Details	Published	Actions
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design Yin Yao Dong , Hua Wang , Ashley C. W. Pike , Stephen A. Cochrane , Sadra Hamedzadeh , Filip J. Wyszyński , Simon R. Bushell , Sylvain F. Royer , David A. Widdick , Andaleeb Sajid , Helena I. Boshoff , Yumi Park , Ricardo Lucas , Wei-Min Liu , Seung Seo Lee , Takuya Machida , Leanne Minall , Shahid Mehmood , Katsiaryna Belaya , Wei-Wei Liu , Amy Chu , Leela Shrestha , Shubhashish M. M. Mukhopadhyay , Claire Strain-Damerell , Rod Chalk , Nicola A. Burgess-Brown , Mervyn J. Bibb , Clifton E. Barry , Carol V. Robinson , David Beeson , Benjamin G. Davis , Elizabeth P. Carpenter Cell 175, 1045 - 1058.e16 DOI: 10.1016/j.cell.2018.10.037 Diamond Proposal Number(s): [10619, 15433, 19301] Open Access Show Abstract ▼ 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.	Nov 2018

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I04-1-Macromolecular Crystallography (fixed wavelength)
I04-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography

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