EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Structures of bacterial and human phosphoglycosyltransferases bound to a common inhibitor inform selective therapeutics.
ジャーナル・号・ページ	bioRxiv, Year 2025
掲載日	2025年12月16日
著者	Beebee Yusrah Kaudeer / Jacob M Kirsh / Katsuhiko Mitachi / Jessica M Ochoa / Marie-Therese Soroush-Pejrimovsky / Yancheng E Li / Vy N Nguyen / Michio Kurosu / William M Clemons /
PubMed 要旨	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 ...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.
リンク	bioRxiv / PubMed:41446129 / PubMed Central
手法	EM (単粒子)
解像度	2.9 - 3.02 Å
構造データ	74451 9znn EMDB-74451: Cryo-EM structure of human UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1) in complex with APPB, composite map PDB-9znn: Cryo-EM structure of human UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1) in complex with APPB 手法: EM (単粒子) / 解像度: 2.9 Å 74452 9zno EMDB-74452, PDB-9zno: Cryo-EM structure of Hydrogenivirga sp. MraY in complex with APPB 手法: EM (単粒子) / 解像度: 2.91 Å EMDB-75257: Cryo-EM structure of human UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1) in complex with APPB, consensus map 手法: EM (単粒子) / 解像度: 2.9 Å EMDB-75258: Cryo-EM structure of human UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1) in complex with APPB, Chain A map 手法: EM (単粒子) / 解像度: 2.91 Å EMDB-75259: Cryo-EM structure of human UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1) in complex with APPB, Chain B map 手法: EM (単粒子) / 解像度: 3.02 Å
化合物	PDB-1c3g: S. CEREVISIAE HEAT SHOCK PROTEIN 40 SIS1 PDB-1c3h: ACRP30 CALCIUM COMPLEX ChemComp-HOH: WATER
由来	homo sapiens (ヒト) hydrogenivirga sp. 128-5-r1-1 (バクテリア)
キーワード	TRANSFERASE / polyprenyl-phosphate N-acetylhexosamine phosphate transferase / phosphoglycosyltransferase / membrane protein / phosphoglycosyltransferases