5URS

Crystal Structure of the Catalytic Domain of the Inosine Monophosphate Dehydrogenase from Bacillus anthracis in the complex with IMP and the inhibitor P178

5URS の概要

• エントリーDOI: 10.2210/pdb5urs/pdb
• 関連するPDBエントリー: 3TSB 3TSD 3USB 4MJM 4MY1 4MY8 4MY9 4MYA 4MYX 4QM1 5urr
• 分子名称: Inosine-5'-monophosphate dehydrogenase, INOSINIC ACID, N-[4-chloro-3-(alpha-D-ribofuranosyloxy)phenyl]-N'-{2-[3-(prop-1-en-2-yl)phenyl]propan-2-yl}urea, ... (9 entities in total)
• 機能のキーワード: impdh, tim barrel, delta cbs, structural genomics, center for structural genomics of infectious diseases, csgid, oxidoreductase
• 由来する生物種: Bacillus anthracis; 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 333135.82

構造登録者

Kim, Y.,Maltseva, N.,Makowska-Grzyska, M.,Gu, M.,Gollapalli, D.,Hedstrom, L.,Anderson, W.F.,Joachimiak, A.,Center for Structural Genomics of Infectious Diseases (CSGID) (登録日: 2017-02-12, 公開日: 2017-03-08, 最終更新日: 2026-03-25)

主引用文献

Modi, G.,Marqus, G.M.,Vippila, M.R.,Gollapalli, D.R.,Kim, Y.,Manna, A.C.,Chacko, S.,Maltseva, N.,Wang, X.,Cullinane, R.T.,Zhang, Y.,Kotler, J.L.M.,Kuzmic, P.,Zhang, M.,Lawson, A.P.,Joachimiak, A.,Cheung, A.,Snider, B.B.,Rothstein, D.M.,Cuny, G.D.,Hedstrom, L.
The Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target for Staphylococcus aureus Infections.
Acs Infect Dis., 7:3062-3076, 2021

PubMed Abstract: Many bacterial pathogens, including , require inosine 5'-monophosphate dehydrogenase (IMPDH) for infection, making this enzyme a promising new target for antibiotics. Although potent selective inhibitors of bacterial IMPDHs have been reported, relatively few have displayed antibacterial activity. Here we use structure-informed design to obtain inhibitors of IMPDH (IMPDH) that have potent antibacterial activity (minimal inhibitory concentrations less than 2 μM) and low cytotoxicity in mammalian cells. The physicochemical properties of the most active compounds were within typical Lipinski/Veber space, suggesting that polarity is not a general requirement for achieving antibacterial activity. Five compounds failed to display activity in mouse models of septicemia and abscess infection. Inhibitor-resistant strains readily emerged . Resistance resulted from substitutions in the cofactor/inhibitor binding site of IMPDH, confirming on-target antibacterial activity. These mutations decreased the binding of all inhibitors tested, but also decreased catalytic activity. Nonetheless, the resistant strains had comparable virulence to wild-type bacteria. Surprisingly, strains expressing catalytically inactive IMPDH displayed only a mild virulence defect. Collectively these observations question the vulnerability of the enzymatic activity of IMPDH as a target for the treatment of infections, suggesting other functions of this protein may be responsible for its role in infection.

PubMed: 34590817
DOI: 10.1021/acsinfecdis.1c00342

実験手法

X-RAY DIFFRACTION (2.388 Å)