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PDBsum entry 5o5e
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References listed in PDB file
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Key reference
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Title
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Structures of dpagt1 explain glycosylation disease mechanisms and advance tb antibiotic design.
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Authors
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Y.Y.Dong,
H.Wang,
A.C.W.Pike,
S.A.Cochrane,
S.Hamedzadeh,
F.J.Wyszyński,
S.R.Bushell,
S.F.Royer,
D.A.Widdick,
A.Sajid,
H.I.Boshoff,
Y.Park,
R.Lucas,
W.M.Liu,
S.S.Lee,
T.Machida,
L.Minall,
S.Mehmood,
K.Belaya,
W.W.Liu,
A.Chu,
L.Shrestha,
S.M.M.Mukhopadhyay,
C.Strain-Damerell,
R.Chalk,
N.A.Burgess-Brown,
M.J.Bibb,
C.E.Barry III,
C.V.Robinson,
D.Beeson,
B.G.Davis,
E.P.Carpenter.
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Ref.
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Cell, 2018,
175,
1045.
[DOI no: ]
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PubMed id
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Abstract
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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.
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