9ZNN

Cryo-EM structure of human UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1) in complex with APPB

これはPDB形式変換不可エントリーです。

9ZNN の概要

• エントリーDOI: 10.2210/pdb9znn/pdb
• EMDBエントリー: 74451
• 分子名称: UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase, 4-({(2S,3S)-1-amino-3-{[(2S,3R,4S,5R)-5-(aminomethyl)-3,4-dihydroxyoxolan-2-yl]oxy}-3-[(2S,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxyoxolan-2-yl]-1-oxopropan-2-yl}amino)-N-[(4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}phenyl)methyl]butanamide (non-preferred name), (2R)-3-{[(S)-[(2R)-2,3-dihydroxypropoxy](hydroxy)phosphoryl]oxy}-2-{[(9Z)-octadec-9-enoyl]oxy}propyl (9Z)-octadec-9-enoate, ... (4 entities in total)
• 機能のキーワード: polyprenyl-phosphate n-acetylhexosamine phosphate transferase, phosphoglycosyltransferase, membrane protein, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 97939.66

構造登録者

Kirsh, J.M.,Ochoa, J.M.,Soroush-Pejrimovsky, M.T.,Kaudeer, B.Y.,Clemons, W.M. (登録日: 2025-12-14, 公開日: 2026-02-04)

主引用文献

Kaudeer, B.Y.,Kirsh, J.M.,Mitachi, K.,Ochoa, J.M.,Soroush-Pejrimovsky, M.T.,Li, Y.E.,Nguyen, V.N.,Kurosu, M.,Clemons Jr., W.M.
Structures of bacterial and human phosphoglycosyltransferases bound to a common inhibitor inform selective therapeutics.
Biorxiv, 2025

PubMed Abstract: Glycoconjugates facilitate myriad biological processes, including cell-cell recognition and immune response, and they are generated by enzymes that transfer glycans. The orthologs MraY and DPAGT1 are dimeric phosphoglycosyltransferases involved in oligosaccharide biosynthesis for either bacterial peptidoglycan or eukaryotic -linked glycans, respectively. Both enzymes play central regulatory roles, making them attractive targets for antibacterial and anticancer therapies. In our prior studies, a muraymycin A1-derived inhibitor termed APPB (aminouridyl phenoxypiperidinbenzyl butanamide) was developed. It exhibits sub-100 nM IC50 values against both MraY and DPAGT1 and has demonstrated efficacy against DPAGT1-dependent cancers, making it an excellent starting point for next-generation small molecules. To guide inhibitor development, we determined cryo-EM structures of APPB bound to MraY or DPAGT1 at 2.9 Å resolution using single-particle analysis. The structures reveal that APPB, composed of a nucleoside, a central amide, and a lipid-mimetic, adopts two conformations in each protein, which correlate with local hydrogen-bonding contacts of the central amide carbonyl. Examination of the amide carbonyl environments guides conformer selection for future DPAGT1-targeting anticancer agents. Further, comparisons of APPB-bound geometries and nucleoside interactions inform opportunities for antibacterial agents targeting MraY. Overall, our study provides design principles for MraY- or DPAGT1-specific drugs and motivates the utility of simultaneously characterizing inhibitor-bound orthologs for selective therapeutics.

PubMed: 41446129
DOI: 10.64898/2025.12.16.694696

実験手法

ELECTRON MICROSCOPY (2.9 Å)