6BW5

Human GPT (DPAGT1) in complex with tunicamycin

6BW5 の概要

• エントリーDOI: 10.2210/pdb6bw5/pdb
• 分子名称: UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase, Tunicamycin, (1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]oxy}-1-[(hexadecanoyloxy)methyl]ethyl (9Z)-octadec-9-enoate (3 entities in total)
• 機能のキーワード: n-linked glycosylation, endoplasmic reticulum, tunicamycin, natural product, transferase, transferase-antibiotic complex, transferase/antibiotic
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 194907.04

構造登録者

Yoo, J.,Kuk, A.C.Y.,Mashalidis, E.H.,Lee, S.-Y. (登録日: 2017-12-14, 公開日: 2018-02-21, 最終更新日: 2024-11-20)

主引用文献

Yoo, J.,Mashalidis, E.H.,Kuk, A.C.Y.,Yamamoto, K.,Kaeser, B.,Ichikawa, S.,Lee, S.Y.
GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation.
Nat. Struct. Mol. Biol., 25:217-224, 2018

PubMed Abstract: N-linked glycosylation is a predominant post-translational modification of protein in eukaryotes, and its dysregulation is the etiology of several human disorders. The enzyme UDP-N-acetylglucosamine:dolichyl-phosphate N-acetylglucosaminephosphotransferase (GlcNAc-1-P-transferase or GPT) catalyzes the first and committed step of N-linked glycosylation in the endoplasmic reticulum membrane, and it is the target of the natural product tunicamycin. Tunicamycin has potent antibacterial activity, inhibiting the bacterial cell wall synthesis enzyme MraY, but its usefulness as an antibiotic is limited by off-target inhibition of human GPT. Our understanding of how tunicamycin inhibits N-linked glycosylation and efforts to selectively target MraY are hampered by a lack of structural information. Here we present crystal structures of human GPT in complex with tunicamycin. Structural and functional analyses reveal the difference between GPT and MraY in their mechanisms of inhibition by tunicamycin. We demonstrate that this difference could be exploited to design MraY-specific inhibitors as potential antibiotics.

PubMed: 29459785
DOI: 10.1038/s41594-018-0031-y

実験手法

X-RAY DIFFRACTION (3.1 Å)