6FWZ

Crystal structure of human UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1) (V264G mutant) in complex with UDP-GlcNAc

Summary for 6FWZ

• Entry DOI: 10.2210/pdb6fwz/pdb
• Descriptor: UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase, MAGNESIUM ION, URIDINE-DIPHOSPHATE-N-ACETYLGLUCOSAMINE, ... (6 entities in total)
• Functional Keywords: protein glycosylation, integral membrane protein, pnpt, congenital myasthenic syndrome, antibiotic, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 47552.37

Authors

Pike, A.C.W.,Dong, Y.Y.,Chu, A.,Tessitore, A.,Goubin, S.,Dong, L.,Mukhopadhyay, S.,Mahajan, P.,Chalk, R.,Berridge, G.,Wang, D.,Kupinska, K.,Belaya, K.,Beeson, D.,Burgess-Brown, N.,Edwards, A.M.,Arrowsmith, C.H.,Bountra, C.,Carpenter, E.P.,Structural Genomics Consortium (SGC) (deposition date: 2018-03-07, release date: 2018-07-25, Last modification date: 2024-01-17)

Primary citation

Dong, Y.Y.,Wang, H.,Pike, A.C.W.,Cochrane, S.A.,Hamedzadeh, S.,Wyszynski, F.J.,Bushell, S.R.,Royer, S.F.,Widdick, D.A.,Sajid, A.,Boshoff, H.I.,Park, Y.,Lucas, R.,Liu, W.M.,Lee, S.S.,Machida, T.,Minall, L.,Mehmood, S.,Belaya, K.,Liu, W.W.,Chu, A.,Shrestha, L.,Mukhopadhyay, S.M.M.,Strain-Damerell, C.,Chalk, R.,Burgess-Brown, N.A.,Bibb, M.J.,Barry Iii, C.E.,Robinson, C.V.,Beeson, D.,Davis, B.G.,Carpenter, E.P.
Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design.
Cell, 175:1045-1058.e16, 2018

PubMed 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.

PubMed: 30388443
DOI: 10.1016/j.cell.2018.10.037

Experimental method

X-RAY DIFFRACTION (3.1 Å)