6fm9

Crystal structure of human UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1)Crystal structure of human UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1)

Structural highlights

6fm9 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	DPAGT1, DPAGT2 (HUMAN)
Activity:	UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase, with EC number 2.7.8.15
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[GPT_HUMAN] DPAGT1-CDG;Congenital myasthenic syndromes with glycosylation defect. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

[GPT_HUMAN] Catalyzes the initial step in the synthesis of dolichol-P-P-oligosaccharides.

Publication Abstract from PubMed

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.

Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design.,Dong YY, Wang H, Pike ACW, Cochrane SA, Hamedzadeh S, Wyszynski FJ, Bushell SR, Royer SF, Widdick DA, Sajid A, Boshoff HI, Park Y, Lucas R, Liu WM, Lee SS, Machida T, Minall L, Mehmood S, Belaya K, Liu WW, Chu A, Shrestha L, Mukhopadhyay SMM, Strain-Damerell C, Chalk R, Burgess-Brown NA, Bibb MJ, Barry Iii CE, Robinson CV, Beeson D, Davis BG, Carpenter EP Cell. 2018 Nov 1;175(4):1045-1058.e16. doi: 10.1016/j.cell.2018.10.037. PMID:30388443^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Dong YY, Wang H, Pike ACW, Cochrane SA, Hamedzadeh S, Wyszynski FJ, Bushell SR, Royer SF, Widdick DA, Sajid A, Boshoff HI, Park Y, Lucas R, Liu WM, Lee SS, Machida T, Minall L, Mehmood S, Belaya K, Liu WW, Chu A, Shrestha L, Mukhopadhyay SMM, Strain-Damerell C, Chalk R, Burgess-Brown NA, Bibb MJ, Barry Iii CE, Robinson CV, Beeson D, Davis BG, Carpenter EP. Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design. Cell. 2018 Nov 1;175(4):1045-1058.e16. doi: 10.1016/j.cell.2018.10.037. PMID:30388443 doi:http://dx.doi.org/10.1016/j.cell.2018.10.037

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Dong YY, Wang H, Pike ACW, Cochrane SA, Hamedzadeh S, Wyszynski FJ, Bushell SR, Royer SF, Widdick DA, Sajid A, Boshoff HI, Park Y, Lucas R, Liu WM, Lee SS, Machida T, Minall L, Mehmood S, Belaya K, Liu WW, Chu A, Shrestha L, Mukhopadhyay SMM, Strain-Damerell C, Chalk R, Burgess-Brown NA, Bibb MJ, Barry Iii CE, Robinson CV, Beeson D, Davis BG, Carpenter EP. Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design. Cell. 2018 Nov 1;175(4):1045-1058.e16. doi: 10.1016/j.cell.2018.10.037. PMID:30388443 doi:http://dx.doi.org/10.1016/j.cell.2018.10.037

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