9AV2

Crystal structure of E. coli GuaB dCBS with inhibitor GNE9979

9AV2 の概要

• エントリーDOI: 10.2210/pdb9av2/pdb
• 分子名称: Inosine-5'-monophosphate dehydrogenase, INOSINIC ACID, N-[4-chloro-3-(dimethylamino)phenyl]-N~2~-[3-(hydroxymethyl)quinolin-6-yl]-L-alaninamide, ... (4 entities in total)
• 機能のキーワード: guab, inhibitor, oxidoreductase
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40650.34

構造登録者

Harris, S.F.,Wu, P. (登録日: 2024-03-01, 公開日: 2025-01-15)

主引用文献

Kofoed, E.M.,Aliagas, I.,Crawford, T.,Mao, J.,Harris, S.F.,Xu, M.,Wang, S.,Wu, P.,Ma, F.,Clark, K.,Sims, J.,Xu, Y.,Peng, Y.,Skippington, E.,Yang, Y.,Reeder, J.,Ubhayakar, S.,Baumgardner, M.,Yan, Z.,Chen, J.,Park, S.,Zhang, H.,Yen, C.-W.,Lorenzo, M.,Skelton, N.,Liang, X.,Chen, L.,Hoag, B.,Li, C.S.,Liu, Z.,Wai, J.,Liu, X.,Liang, J.,Tan, M.W.
Discovery of GuaB inhibitors with efficacy against Acinetobacter baumannii infection.
Mbio, 15:e0089724-e0089724, 2024

PubMed Abstract: Guanine nucleotides are required for growth and viability of cells due to their structural role in DNA and RNA, and their regulatory roles in translation, signal transduction, and cell division. The natural antibiotic mycophenolic acid (MPA) targets the rate-limiting step in guanine nucleotide biosynthesis executed by inosine-5´-monophosphate dehydrogenase (IMPDH). MPA is used clinically as an immunosuppressant, but whether inhibition of bacterial IMPDH (GuaB) is a valid antibacterial strategy is controversial. Here, we describe the discovery of extremely potent small molecule GuaB inhibitors (GuaBi) specific to pathogenic bacteria with a low frequency of on-target spontaneous resistance and bactericidal efficacy against mouse models of infection. The spectrum of GuaBi activity includes multidrug-resistant pathogens that are a critical priority of new antibiotic development. Co-crystal structures of , and GuaB proteins bound to inhibitors show comparable binding modes of GuaBi across species and identifies key binding site residues that are predictive of whole-cell activity across both Gram-positive and Gram-negative clades of Bacteria. The clear efficacy of these small molecule GuaB inhibitors in a model of infection validates GuaB as an essential antibiotic target.

PubMed: 39207111
DOI: 10.1128/mbio.00897-24

実験手法

X-RAY DIFFRACTION (1.7 Å)