9YNP

Cryo-EM structure of Escherichia coli transcription initiation complex with GpA and pseudouridimycin (PUM)

9YNP の概要

• エントリーDOI: 10.2210/pdb9ynp/pdb
• EMDBエントリー: 73220
• 分子名称: DNA-directed RNA polymerase subunit alpha, MAGNESIUM ION, (1S)-1,4-anhydro-5-[(N-carbamimidoylglycyl-N~2~-hydroxy-L-glutaminyl)amino]-5-deoxy-1-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-D-ribitol, ... (11 entities in total)
• 機能のキーワード: transcription initiation complex, pseudouridimycin (pum), inhibitor, antibacterial agent, transcription, transferase-dna-rna-inhibitor complex, transferase/dna/rna/inhibitor
• 由来する生物種: Escherichia coli str. K-12 substr. MG1655; 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 476063.42

構造登録者

You, L.L.,Ebright, R.H. (登録日: 2025-10-11, 公開日: 2026-04-08)

主引用文献

Anwar, A.F.,You, L.,Degen, D.,Burns, K.J.,Garza, M.J.,Ebright, R.H.,Del Valle, J.R.
Solid-phase synthesis and biological evaluation of des-hydroxy pseudouridimycin analogs.
Acs Med.Chem.Lett., 2026

PubMed Abstract: Pseudouridimycin (PUM) is a C-nucleoside/peptide antibiotic that selectively inhibits bacterial RNA polymerase (RNAP) and exhibits potent activity against drug-resistant pathogens. However, PUM suffers from chemical instability due to self-immolative cleavage of its central hydroxamate bond. Here, we employed cryo-electron microscopy to determine structures of PUM () and a chemically stabilized des-hydroxy analog of PUM () bound to an RNAP transcription complex. Guided by the observed bound conformation, we developed an efficient solid-phase synthesis of 50 des-hydroxy PUM analogs modified at the Gln residue and Gdn-Gly tail. Several analogs retained low-micromolar RNAP-inhibitory activity, with a -substituted phenyl amidine analog () emerging as the most potent inhibitor (IC = 0.95 μM). These results establish a versatile synthetic platform and structural framework for optimizing stabilized PUM derivatives and provide a foundation for the development of RNAP-targeted therapeutics against resistant bacterial pathogens.

PubMed: 41890570
DOI: 10.1021/acsmedchemlett.5c00684

実験手法

ELECTRON MICROSCOPY (3.06 Å)